Silvia Ghione

Nesrine Mabrouk

Catherine Paul

Ali Bettaieb

Stéphanie Plenchette
email: stephanie.plenchette@u-bourgogne.fr

Protein kinase inhibitor-based cancer therapies: Considering the potential of nitric oxide (NO) to improve cancer treatment

Keywords: kinase, kinase inhibitor, cancer, nitric oxide, post-translational modification

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Phosphorylation events are the most common and extensively studied protein posttranslational modifications in mammalian systems. Coordinated by a large and diverse family of kinases, phosphorylation is a pivotal biochemical phenomenon involved in signal transduction and multiple cellular functions including cell survival, differentiation, proliferation and migration. The human kinome, which comprises approximately 535 protein kinases, controls many signaling pathways and their crosstalk that leads to virtually all fundamental biological processes [START_REF] Wilson | New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome[END_REF][START_REF] Ardito | The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (Review)[END_REF]. It is now well established that protein kinase activities disorders exert a crucial role in cancer development and progression [3]. As such, protein kinases are frequently found to be oncogenic by distinct mechanisms including somatic mutations, chromosomal translocation, amplification and also epigenetic regulation [START_REF] Tsatsanis | The role of oncogenic kinases in human cancer (Review)[END_REF]. Since, many efforts have been made to develop new therapeutic strategies to restrict protein kinase activities for clinical application in oncology.

In the past two decades, a wide range of protein kinase inhibitors (PKIs) types, with various properties and mode of action i.e including different selectivity and modes of binding to kinases, have entered different phases of clinical development and several are currently approved by the FDA. Thus, PKIs have become a major class of cancer drugs and their therapeutic potential is still an area of increased interest. Indeed, the study of kinase biology associated with the development of PKIs is a significant component of targeted therapies.

Despite encouraging clinical benefits for patients, the use of PKIs, as cancer therapeutics, remains frequently overshadowed by drug resistance mechanisms [START_REF] Kannaiyan | A comprehensive review of protein kinase inhibitors for cancer therapy[END_REF].

The dynamic evolution of cancer cells reflected by constant acquired mutations and genomic instability toward various protein kinases has a dramatic impact on PKI-based therapy effectiveness. The ability of cancer cells to resist to PKI therapies gives rise to a need to develop new therapeutic options. For this reason, new generation PKIs were developed and tested in an attempt to overcome resistance. Despite therapeutic benefit of PKIs to cancer patients, primary and acquired resistance still represent a major challenge in kinasetargeted drug development for cancer therapy. New combinatorial PKI-based approach that would selectively target cancer cells would open new therapeutic windows to neutralize cancer cell evasion from targeted therapies. Basically, two possible approaches might be considered to lower cancer cell resistance to PKI. Combinatorial strategies of PKI with drugs that would target the same protein kinase or alternate signaling pathways. As a key posttranslational modification, protein phosphorylation has been the foundation for signal transduction therapy for cancer. Beside phosphorylation, a number of proteins involved in signal transduction pathways are also a target of a multitude of other post-translational modifications such as glycosylation, ubiquitination, SUMOylation, acetylation or methylation among others, revealing a complex regulatory network. Such post-translation modifications modulating cellular signaling represent putative antitumor strategies that could be considered along the use of PKI.

Nitric oxide (NO)-mediated protein post-translation modifications have gained increasing consideration in the context of cancer. Studies have demonstrated that NO can regulate many classes of protein associated with signaling pathways involved either in cancer development, progression or inhibition [START_REF] Plenchette | NO and cancer: itinerary of a double agent[END_REF][START_REF] Plenchette | S-Nitrosylation in TNF superfamily signaling pathway: Implication in cancer[END_REF][START_REF] Bettaieb | S-Nitrosylation in Cancer Cells: To Prevent or to Cause?[END_REF]. Several features such as localization, concentration, cellular time exposure or the redox environment dictate the complex dichotomous action of NO in cancers : either pro-tumoral or anti-tumoral [START_REF] Vasudevan | Insights into the diverse effects of nitric oxide on tumor biology[END_REF]. NO production is generally assumed to play a crucial role in cancer cell fate decisions. Low rate of NO can contribute to tumorigenesis and progression whereas high rate of NO can promote cancer cell death [START_REF] Burke | The yin and yang of nitric oxide in cancer progression[END_REF][START_REF] Foster | Protein S-nitrosylation in health and disease: a current perspective[END_REF][START_REF] Ridnour | The biphasic nature of nitric oxide responses in tumor biology[END_REF]. The insights gained into NO mode of action revealed that both Snitrosylation (the covalent binding of NO moiety to a free cysteine of target protein), and nitration (the covalent binding of NO moiety to a tyrosine residue) are key regulatory protein post-translational modifications in cellular signaling.

As a highly selective and rapidly reversible protein post-translational modification, Snitrosylation has probably one of the most significant biochemical impact over protein function inducing multiple changes in protein activity, conformation, localization or interaction with other protein partners [START_REF] Plenchette | NO and cancer: itinerary of a double agent[END_REF]. Enzymes are a class of protein frequently targeted by NO. Although protein post-translational modifications induced by NO has the ability to both activate or inhibit kinases, a wide range of enzymes involved in cell survival, proliferation or cell death signaling pathways are negatively regulated by NO posttranslation modifications [START_REF] Plenchette | NO and cancer: itinerary of a double agent[END_REF].

The purpose of this review is to survey the PKIs from the perspective of how NO could have a beneficial anti-tumoral effect on PKI-based therapies. The current review will discuss the link between PKIs and NO with the aim of considering NO as potential novel combination therapies using PKIs and NO donors.

I. Background on the main PKIs

The discovery of PKIs and their clinical use have revolutionized targeted therapy in cancer. The real benefit of PKIs over conventional chemotherapy, results in less cytotoxicity for non-cancerous cells because of more selectivity and lower toxic manifestations. Despite the low toxicity, these molecules have specific toxicity profile, and the understanding of the mechanisms of action is necessary to understand this process [START_REF] Davies | Specificity and mechanism of action of some commonly used protein kinase inhibitors[END_REF][START_REF] Druker | Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia[END_REF].

The development of imatinib, the first PKI used in cancer therapy, allows to block the kinase activity of the aberrant protein breakpoint cluster region-protein Abelson (Bcr-Abl, characterized by a chromosomic translocation between chromosome 9 and chromosome 22 in the hematological malignancy chronic myeloid leukemia (CML)), and increases overall survival (OS). Because Bcr-Abl recombination is a driver oncogenic process in CML, patients are more sensitive to PKIs-based therapies than for patients with solid tumors because of high heterogeneity and mutational rate [START_REF] Pishvaian | A Phase I clinical trial of the combination of imatinib and paclitaxel in patients with advanced or metastatic solid tumors refractory to standard therapy[END_REF]. Imatinib is not specific for Bcr-Abl kinase, and target other oncogenic kinases. Then, imatinib (STI-571) is approved by the FDA not only for the treatment of CML but also for gastrointestinal stromal tumors (GIST) harbouring c-Kit mutation [START_REF] Kannaiyan | A comprehensive review of protein kinase inhibitors for cancer therapy[END_REF][START_REF] Demetri | Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors[END_REF][START_REF] Druker | Translation of the Philadelphia chromosome into therapy for CML[END_REF] and dermatofibrosarcoma protuberans [START_REF] Pishvaian | A Phase I clinical trial of the combination of imatinib and paclitaxel in patients with advanced or metastatic solid tumors refractory to standard therapy[END_REF][START_REF] Mcarthur | Dermatofibrosarcoma protuberans: a surgical disease with a molecular savior[END_REF]. Imatinib is able to block the tyrosine kinase activity because it is an ATP competitor, which can interact with the inactive catalytic site of the kinase [START_REF] Kufareva | Type-II kinase inhibitor docking, screening, and profiling using modified structures of active kinase states[END_REF][START_REF] Suttorp | Pharmacology and pharmacokinetics of imatinib in pediatric patients[END_REF]. Other PKIs have the same mechanism of action, such as sorafenib, which is a multi-kinase inhibitor that blocks various kinases such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), BRAF and c-Kit [START_REF] Gounder | Sorafenib for Advanced and Refractory Desmoid Tumors[END_REF]. Because of his multi-target activity, sorafenib is actually used for the treatment of GISTs such as imatinib [START_REF] Rutkowski | The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST) after imatinib failure -one institution study[END_REF]. Levatinib and regorafenib have the same mechanism of action. The first one principally inhibits VEGFR, and is approved for the treatment of iodine-refractory differentiated thyroid cancer and metastatic renal cell carcinoma (RCC) [START_REF] Capozzi | Lenvatinib, a molecule with versatile application: from preclinical evidence to future development in anti-cancer treatment[END_REF]. Regorafenib also targets VEGFR, PDGFR and BRAF and is mainly used for the treatment of advanced GIST, advanced hepatocellular carcinoma (HCC) and advanced colorectal carcinoma (CRC) [START_REF] Ettrich | Regorafenib[END_REF].

Other PKIs, such as gefitinib, sunitinib and vemurafenib, are also ATP competitors [START_REF] Liu | Rational design of inhibitors that bind to inactive kinase conformations[END_REF].

Gefinitib is used to block the activation of mutated tyrosine kinase receptor EGFR (either deleted in exon 19 or L858R point mutated within exon 21) in NSCLC resulting in permanent activation of the ATP-binding site in absence of the ligand [START_REF] Rahman | Gefitinib[END_REF]. Sunitinib is not specific to endothelial growth factor receptor (EGFR), but can also inhibit VEGFR and c-Kit and for this reason, it can be used to treat GISTs in people who do not respond to imanibib treatment [START_REF] Yang | Clinical outcomes of imatinib dose escalation versus sunitinib in first-line imatinib-failure gastrointestinal stromal tumour[END_REF]. More recently, FDA approves osimertinib as first-line treatment of metastatic NSCLC patients based on the FLAURA trial [START_REF] Ohe | Osimertinib versus standard-of-care EGFR-TKI as first-line treatment for EGFRm advanced NSCLC: FLAURA Japanese subset[END_REF]. vemurafenib is used in patients with BRAF V600E mutated melanoma. This mutation can switch-on the serine/threonine kinase activity, with an abnormal activation of the mitogen-activated protein kinase (MAPK)/extracellular signalregulated kinases (ERK) proliferating signaling pathway. vemurafenib block the activation of the mutated protein, stopping cancer cells proliferation. Unfortunately, this drug shows side effects on healthy cells. Indeed, vemurafenib also targets the wild type form of BRAF, causing a kinase overactivation of MAPK/ERK signaling pathway in healthy cells. Despite this side effect, vemurafenib is an established efficient therapy [START_REF] Zhang | Clinical Pharmacokinetics of Vemurafenib[END_REF][START_REF] Thakur | Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance[END_REF].

Some PKI can block the kinase activity in an allosteric manner, by binding outside the catalytic ATP-binding site such as trametinib, a mitogen extracellular kinases (MEK) inhibitor [START_REF] Lamba | New directions in targeting protein kinases: focusing upon true allosteric and bivalent inhibitors[END_REF][START_REF] Zeiser | Trametinib (GSK1120212)[END_REF]. Another mechanism of action relies on the covalent bond between the PKI and the catalytic site of the kinase, as for ibrutinib, a bruton tyrosine kinase (BTK) inhibitor [START_REF] Deeks | Ibrutinib: A Review in Chronic Lymphocytic Leukaemia[END_REF][START_REF] Cohen | Structural bioinformatics-based design of selective, irreversible kinase inhibitors[END_REF].

Even though PKIs increase OS in many cancer subtypes, primary and secondary resistances are still frequently observed. Numerous potential mechanisms of resistance to PKIs have been described, requiring the use of second, third or fourth generation PKIs for patients refractory to treatment. Therefore, the development of novel combinational therapies may represent an attractive way to overcome PKI-resistant cancer cells [START_REF] Rexer | Overcoming resistance to tyrosine kinase inhibitors: lessons learned from cancer cells treated with EGFR antagonists[END_REF].

II. Clinical use of the main PKIs in cancer 1. Bcr-Abl tyrosine kinase inhibitors a. CML

The clinical development of imatinib has been a considerable leap in CML therapy. Indeed, in a phase II study involving 452 patients with CML who had failed to respond to interferon α therapy, Kantarjian et al. demonstrated that imatinib treatment induced high rates of cytogenetic (60% of patients) and hematologic responses (95% of patients).

Moreover, after a median follow-up of 18 months, 95% of patients were alive [START_REF] Kantarjian | Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia[END_REF]. The last update of the ISIS study comparing interferon treatment versus imatinib (ISIS: international randomized study of interferon versus STI-571) showed an estimated OS of 83% at 10 years [START_REF] Gugliotta | Long-term outcome of a phase 2 trial with nilotinib 400 mg twice daily in first-line treatment of chronic myeloid leukemia[END_REF].

Imatinib resistance mechanisms were classified according to two criteria: Bcr-Abl dependent and independent mechanisms [START_REF] Ramirez | Therapy options in imatinib failures[END_REF]. Bcr-Abl dependent mechanisms of resistance are associated with different point mutations which totally or partially impair the catalytic domain of Bcr-Abl or the imatinib-binding sites to this kinase. Almost 57 residues were identified, mostly in the ATP-binding loop (P-loop), the SH2 binding site, and the A-loop, which then dictate the efficacy of imatinib but also future therapeutic strategies to overcome imatinib-resistance [START_REF] Deininger | The development of imatinib as a therapeutic agent for chronic myeloid leukemia[END_REF][START_REF] Soverini | BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet[END_REF]. Because of patients refractory to imatinib treatment, more PKIs were FDA-approved for the treatment of CML such as dasatinib (inhibitor of c-KIT, PDGFR-A and B for example) [START_REF] Schittenhelm | Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies[END_REF][START_REF] Lombardo | Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays[END_REF], nilotinib and bosutinib, three second generation PKIs.

Another example, ponatinib, a third generation PKI is used to overcome T315I mutation (a frequent Bcr-Abl resistance mutation) not only for imatinib-resistant patients [START_REF] La Rosée | Activity of the Bcr-Abl kinase inhibitor PD180970 against clinically relevant Bcr-Abl isoforms that cause resistance to imatinib mesylate (Gleevec, STI571)[END_REF] but also for patients refractory to treatment with multiple PKIs [START_REF] Kannaiyan | A comprehensive review of protein kinase inhibitors for cancer therapy[END_REF].

The ABL gene deletion in 9q is another mechanism of imatinib resistance and poor prognosis in CML [START_REF] Huntly | Deletions of the derivative chromosome 9 occur at the time of the Philadelphia translocation and provide a powerful and independent prognostic indicator in chronic myeloid leukemia[END_REF][START_REF] Sinclair | Large deletions at the t(9;22) breakpoint are common and may identify a poorprognosis subgroup of patients with chronic myeloid leukemia[END_REF]. Moreover, microRNAs (miRNAs) such as miR-199b and miR-219-2 (centromeric to the Abl gene frequently lost in CML patients) were downregulated in patients bearing 9q deletion and associated with imatinib resistance [START_REF] Joshi | Down-regulation of miR-199b associated with imatinib drug resistance in 9q34.1 deleted BCR/ABL positive CML patients[END_REF].

b. GIST

Imatinib has also revolutionized the medical treatment of KIT-driven GISTs. In a randomized phase III, Dematteo et al. showed that imatinib significantly improved recurrence-free survival compared with placebo (98% vs 83%) at 1 year [START_REF] Dematteo | Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial[END_REF]. Moreover, in another randomized phase III study including patients with KIT-positive GIST showed that, compared with a 1-year only treatment, post-operative imatinib administered for 3 years allowed longer recurrence-free survival (RFS) (47.9 vs 65.6% respectively) and longer OS (81.7% vs 92%, respectively) [START_REF] Joensuu | One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial[END_REF].

Furthermore, it has been shown that mutations in KIT or PDGFRA were frequently found in GISTs patients that are primary refractory to imatinib. These mutations seem to be present within an exon that renders the protein less sensitive to imatinib, and contribute then to the development of drug resistance [START_REF] Heinrich | Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor[END_REF].

EGFR tyrosine kinase inhibitors

a. NSCLC It is recognized that EGFR is overexpressed in ~80% and mutated in 20% of NSCLC [START_REF] Lynch | Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib[END_REF][START_REF] Pao | Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer[END_REF]. Phosphorylation of EGFR (e.g. Y1173; Y1068; Y1045; and Y854 residues) is required to initiate cellular signaling [START_REF] Gazdar | Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors[END_REF]. EGFR tyrosine kinase inhibitors (EGFR-TKIs) such as erlotinib, gefitinib and afatinib (non-exhaustive list) are widely used in cancer treatment.

Erlotinib was the first EGFR-TKI assessed as first-line treatment for patients with NSCLC with EGFR mutations [START_REF] Kannaiyan | A comprehensive review of protein kinase inhibitors for cancer therapy[END_REF][START_REF] Rosell | Nonsmall-cell lung cancer harbouring mutations in the EGFR kinase domain[END_REF]. In the EURTAC randomized phase III trial, erlotinib treatment showed beneficial results with a progression-free survival (PFS) of 9.7 months compared to standard chemotherapy with a PFS of 5.2 months [START_REF] Rosell | Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial[END_REF]. Gefitinib is also a first-generation EGFR-TKIs approved by FDA in 2015 for treatment of NSCLC patients with EGFR mutations. Indeed, Douillard et al. showed in a phase IV clinical trial that gefitinib as a first line treatment was effective and well tolerated in patients with stage IIIa/B/IV EGFR mutationpositive NSCLC [START_REF] Douillard | Firstline gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study[END_REF]. Afatinib is a second-generation EGFR TKI and the first irreversible oral blocker of the ErbB family. This TKI has been approved by the FDA for the treatment of locally advanced or metastatic patients with NSCLC after the two randomized phase III studies Lux-Lung3 and Lux-lung6. In these studies, afatinib improves overall survival only in patients with del19EGFR mutations (33.3 months vs 21.1 months in the chemotherapy group) [START_REF] Yang | Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial[END_REF].

Many acquired resistance mechanisms to gerfitinib, erlotinib and afatinib EGFR-TKIs have been reported and can be classified into three categories: target gene mutation, bypass signaling pathway activation and histological transformation [START_REF] Gao | Strategies to overcome acquired resistance to EGFR TKI in the treatment of non-small cell lung cancer[END_REF][START_REF] Nagano | Mechanism of Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors and a Potential Treatment Strategy[END_REF]. The main mechanism of EGFR-TKIs resistance arises from the site mutation T790M in EGFR (detected in 50-60% of resistant cases), which prevents EGFR-TKIs binding [START_REF] Kobayashi | EGFR mutation and resistance of non-small-cell lung cancer to gefitinib[END_REF][START_REF] Camidge | Acquired resistance to TKIs in solid tumours: learning from lung cancer[END_REF][START_REF] Uchibori | Phase II trial of gefitinib plus pemetrexed after relapse using first-line gefitinib in patients with non-small cell lung cancer harboring EGFR gene mutations[END_REF]. Importantly, osimertinib has been found to prolong the survival for metastatic NSCLC patients with EGFR mutations (with or without the T790M mutation) [START_REF] Hu | Clinical efficacy analysis of Osimertinib treatment for a patient with leptomeningeal metastasis of EGFR+ non-small cell lung cancer without the T790M mutation[END_REF].

VEGFR tyrosine kinase inhibitors

Several VEGFR-TKIs have been developed and used to treat different types of cancer. These PKIs include (but are not limited to) sorafenib, sunitinib, pazopanib, cabozantinib, lenvatinib, vandetanib, regorafenib, as multi-targeted TKIs, and axitinib as the only VEGFR specific inhibitor.

a. Sorafenib

As a non-specific inhibitor, sorafenib can also target PDGFRs, FLT3 receptor, BRAF, RET and c-kit [START_REF] Escudier | Sorafenib in advanced clear-cell renal-cell carcinoma[END_REF]. Sorafenib has been the first TKI approved by the FDA for the treatment of RCC in 2005, based on the positive results of the randomized phase III TARGET trial. In this clinical trial, the sorafenib group was compared with a placebo group in a cohort of 903 patients with RCC that was resistant to standard therapy. PFS for these patients was significantly prolonged (5.5 months vs 2.8 months for placebo) [START_REF] Escudier | Sorafenib in advanced clear-cell renal-cell carcinoma[END_REF]. This TKI is also used in HCC patients. Indeed, in a multicenter phase III trial, patients with advanced HCC receiving sorafenib had median survival, as well as time to radiologic progression nearly 3 months longer than patients receiving placebo [START_REF] Llovet | Sorafenib in advanced hepatocellular carcinoma[END_REF].

However, multiple mechanisms that lead to sorafenib resistance have been reported including for example EGFR, Akt or c-Jun activation [START_REF] Niu | New insights into sorafenib resistance in hepatocellular carcinoma: Responsible mechanisms and promising strategies[END_REF][START_REF] Zhu | New knowledge of the mechanisms of sorafenib resistance in liver cancer[END_REF]. Furthermore, cancer stem cells, Src homology 2 domain-containing phosphatase 2 (Shp2) and upregulation of fibroblast growth factor (FGF) signaling pathway may also play a role [START_REF] Zhu | New knowledge of the mechanisms of sorafenib resistance in liver cancer[END_REF]. As described for imatinib drug resistance, some miRNAs such as miR-181a [START_REF] Azumi | miR-181a induces sorafenib resistance of hepatocellular carcinoma cells through downregulation of RASSF1 expression[END_REF], and miR-429 [START_REF] Li | Epigenetic modification of MiR-429 promotes liver tumour-initiating cell properties by targeting Rb binding protein 4[END_REF] can also be responsible for drug resistance.

Yet, some drug combination therapies have been used successfully. Sorafenib combined with capecitabine, in advanced solid tumors, including HCC, improved anti-tumor response and survival [START_REF] Patt | Phase II Trial of Sorafenib in Combination with Capecitabine in Patients with Hepatocellular Carcinoma: INST 08-20[END_REF]. In addition, a phase II clinical trial combining sorafenib with doxorubicine shows a synergistically inhibition of tumor cells proliferation and new blood vessels formation in tumor nodules [START_REF] Abou-Alfa | Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial[END_REF]. Moreover, combination of sorafenib with low-dose of 5fluorouracil (5-FU) in HCC patients showed a positive response, which could reduce adverse effects by decreasing 5-FU dose intensity [START_REF] Zhu | New knowledge of the mechanisms of sorafenib resistance in liver cancer[END_REF]. Other combinatory strategies reported better curative effect with decreased side effects, as uracil-tegafur [START_REF] Hsu | Phase II study of combining sorafenib with metronomic tegafur/uracil for advanced hepatocellular carcinoma[END_REF] or octreotide [START_REF] Prete | Sorafenib plus octreotide is an effective and safe treatment in advanced hepatocellular carcinoma: multicenter phase II So.LAR. study[END_REF].

Furthermore, a clinical trial in patients with castration-resistant prostate cancer, reported that sorafenib can be combined safely with chemotherapy [START_REF] Meyer | Role of sorafenib in overcoming resistance of chemotherapy-failure castration-resistant prostate cancer[END_REF].

b. Sunitinib

Sunitinib is also a non-specific tyrosine kinase inhibitor approved by the FDA for the treatment of metastatic RCC and imatinib-resistant GIST based on the results of several randomized phase III trials [START_REF] Motzer | Sunitinib versus interferon alfa in metastatic renal-cell carcinoma[END_REF][START_REF] Demetri | Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial[END_REF].

However, sunitinib efficacy appeared to be influenced by primary KIT gene mutations (located in exon 11) [START_REF] Rutkowski | The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST) after imatinib failure -one institution study[END_REF][START_REF] Heinrich | Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor[END_REF][START_REF] Yoon | Sunitinib as a second-line therapy for advanced GISTs after failure of imatinib: relationship between efficacy and tumor genotype in Korean patients[END_REF] and secondary mutations in KIT exons 17 or 18 [START_REF] Heinrich | Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor[END_REF][START_REF] Gajiwala | KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients[END_REF][START_REF] Nishida | Sunitinib-resistant gastrointestinal stromal tumors harbor cis-mutations in the activation loop of the KIT gene[END_REF][START_REF] Gao | Secondary mutations of c-KIT contribute to acquired resistance to imatinib and decrease efficacy of sunitinib in Chinese patients with gastrointestinal stromal tumors[END_REF].

Furthermore, Tran et al., showed that sunitinib resistance was correlated with the upregulation of FGF1, in RCC cell line [START_REF] Tran | Fibroblast Growth Factor Receptor-Dependent and -Independent Paracrine Signaling by Sunitinib-Resistant Renal Cell Carcinoma[END_REF]. Alterations in some miRNAs expression either increased (miR-575, miR-642b-3p, miR-4430) or decreased (miR-18a-5p, miR-29b-1-5p, miR-431-3p, miR-4521) were associated with sunitinib resistance. [START_REF] Yamaguchi | Identification of MicroRNAs Involved in Resistance to Sunitinib in Renal Cell Carcinoma Cells[END_REF]. regorafenib is another TKI with an activity against VEGFR, but also KIT, PDGFRA and BRAF used as a third line therapy for GISTs patients refractory to imatinib and sunitinib treatment that was found to increase PFS [START_REF] Wilhelm | Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity[END_REF][START_REF] Saito | Treatment of Regorafenib in Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumor after Failure of Imatinib and Sunitinib[END_REF][START_REF] Zhang | Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumor after failure with imatinib and sunitinib treatment: A meta-analysis[END_REF][START_REF] Demetri | Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebocontrolled, phase 3 trial[END_REF]. Tomida and collaborators, showed that the blockade of VEGFR by regorafenib, stimulates PDGFR and FGF receptor (FGFR) activation and increases cancer cells malignancy [START_REF] Tomida | Regorafenib induces adaptive resistance of colorectal cancer cells via inhibition of vascular endothelial growth factor receptor[END_REF].

c. Lenvatinib

Lenvatinib (Lenvima®) is approved since February 2015 by the FDA for the treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC) [START_REF] Kiyota | Defining Radioiodine-Refractory Differentiated Thyroid Cancer: Efficacy and Safety of Lenvatinib by Radioiodine-Refractory Criteria in the SELECT Trial[END_REF]. This drug is generally a well-tolerated treatment that offers a good alternative to sorafenib (because of its ability to stop the epithelial to mesenchymal transition (EMT) process in combination with the histone desacetylase inhibitor HNHA), another PKI currently approved in RR-DTC [START_REF] Frampton | Lenvatinib: A Review in Refractory Thyroid Cancer[END_REF][START_REF] Lee | Anti-cancer Effects of HNHA and Lenvatinib by the Suppression of EMT-Mediated Drug Resistance in Cancer Stem Cells[END_REF].

Furthermore, most patients with diffuse thyroid diseases develop resistance to lenvatinib, with two principal mechanisms: upregulation of receptors (such as c-Met) or activation of alternative pathways (MEK and phosphoinositide-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathways) [START_REF] Rexer | Overcoming resistance to tyrosine kinase inhibitors: lessons learned from cancer cells treated with EGFR antagonists[END_REF][START_REF] Luo | Redundant kinase activation and resistance of EGFR-tyrosine kinase inhibitors[END_REF][START_REF] Saji | The PI3K-Akt-mTOR pathway in initiation and progression of thyroid tumors[END_REF][START_REF] Ghidini | Clinical development of mTor inhibitors for renal cancer[END_REF][START_REF] Shojaei | HGF/c-Met acts as an alternative angiogenic pathway in sunitinibresistant tumors[END_REF][START_REF] Sennino | Controlling escape from angiogenesis inhibitors[END_REF].

BRAF-V600E

BRAF mutations are common in cancer cells, with BRAF V600E mutation being the most frequent one, particularly in melanoma (nearly 50% of patients affected) [START_REF] Zhang | The genomic landscape of cutaneous melanoma[END_REF][START_REF] Menzies | Distinguishing clinicopathologic features of patients with V600E and V600K BRAFmutant metastatic melanoma[END_REF][START_REF] Davies | Mutations of the BRAF gene in human cancer[END_REF]. Even though the FDA approved vemurafenib in 2011 for the treatment of metastatic melanoma associated with BRAF V600E mutation, a short term increase in patient survival and secondary resistance quickly appears [START_REF] Chapman | Improved survival with vemurafenib in melanoma with BRAF V600E mutation[END_REF]. Overactivation of MAPK/ERK or PI3K/Akt/mTOR signaling pathways, either driven by upstream receptors (EGFR, FGFR and PDGFR) or by alteration of component of signal cascades confer resistance to BRAF V600E mutated tumor cells [START_REF] Shaffer | Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance[END_REF][START_REF] Nazarian | Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation[END_REF][START_REF] Shao | BH3-only protein silencing contributes to acquired resistance to PLX4720 in human melanoma[END_REF][START_REF] Komatsu | mTORC1 upregulation via ERK-dependent gene expression change confers intrinsic resistance to MEK inhibitors in oncogenic KRas-mutant cancer cells[END_REF][START_REF] Hu | AEBP1 upregulation confers acquired resistance to BRAF (V600E) inhibition in melanoma[END_REF]. Jazirehi and coworkers showed also KIT proto-oncogene receptor tyrosine kinase and MET expression in resistant cell lines [START_REF] Jazirehi | Aberrant apoptotic machinery confers melanoma dual resistance to BRAF(V600E) inhibitor and immune effector cells: immunosensitization by a histone deacetylase inhibitor[END_REF]. Of note, the association of BRAF and MEK inhibitors represent a new strategy to treat metastatic melanoma resistant to vemurafenib [START_REF] Welsh | Resistance to combination BRAF and MEK inhibition in metastatic melanoma: Where to next?[END_REF].

III. Regulatory relationships between protein kinases, PKIs and NO in cancer

It is worthy to note that there is little knowledge available with regard to the relationship between protein kinases, their inhibitors and NO. Nevertheless, some arguments are in favor of a complex regulatory network in which PKIs may exert an influence on endogenous production of NO, and on the other way round, NO (from other sources, mainly NO donors) may have an impact on protein kinases. We reviewed the role of NO as a negative and positive regulator of protein kinases to evaluate whether NO could provide added value to the action of PKIs in cancer to ultimately overcome PKIs-mediated resistance (Figure 1).

Involvement of NO in PKIs-mediated antitumor potential

It was reported that mTOR inhibitors such as rapamycin and RAD001 increased Furthermore, axitinib inhibited the expression of iNOS in MDSC cells affecting their immunosuppressive function [START_REF] Zhang | Axitinib, a selective inhibitor of vascular endothelial growth factor receptor, exerts an anticancer effect in melanoma through promoting antitumor immunity[END_REF]. A translational study determined the NO levels in CML patients after imatinib therapy, one of the most effective treatment for Bcr-Abl + CML patients. In this study, the authors showed that the imatinib decreased the plasma level of NO by three times (41.48 to 14.26 µmol/L). The authors concluded that NO levels might be used as a prognostic indicator in CML patients treated with imatinib [START_REF] Ghalaut | Effect of imatinib therapy with and without turmeric powder on nitric oxide levels in chronic myeloid leukemia[END_REF].

While cancer treatment with the kinase inhibitors listed above decreases the NO level, other kinase inhibitors have the opposite effect, exemplified by vemurafenib and sorafenib. On the one hand, Yu et al. reported that vemurafenib initiates apoptosis and growth inhibition of BRAF V600E mutant human melanoma cell line A375, which is correlated with vemurafenib-inducing production of intracellular NO [START_REF] Yu | Involvement of superoxide and nitric oxide in BRAF(V600E) inhibitor PLX4032-induced growth inhibition of melanoma cells[END_REF]. Such effect was abolished with NG-monomethyl-L-arginine monoacetate (L-NMMA), an iNOS inhibitor [START_REF] Yu | Involvement of superoxide and nitric oxide in BRAF(V600E) inhibitor PLX4032-induced growth inhibition of melanoma cells[END_REF].

Caraglia et al. showed that in patients with advanced HCC, sorafenib induced an increase of 40% of serum NO levels [START_REF] Caraglia | Oxidative stress and ERK1/2 phosphorylation as predictors of outcome in hepatocellular carcinoma patients treated with sorafenib plus octreotide LAR[END_REF]. This effect was observed only in sensitive patients to the treatment [START_REF] Caraglia | Oxidative stress and ERK1/2 phosphorylation as predictors of outcome in hepatocellular carcinoma patients treated with sorafenib plus octreotide LAR[END_REF]. Thereby, the determination of the NO status in patient's serum could have high value in the prediction of response to sorafenib therapy in HCC patients.

NO favours PKIs toxicity

It is a proven fact that the use of PKIs, as well as antibodies directed against tumorinducing signaling pathways, has shown very beneficial effects in several types of cancer.

However, this benefit is associated with some toxicities. We will focus on those involving NO, known to regulate blood pressure. Indeed, whether many PKIs induced hypertension some others do the opposite. It is well documented that bevacizumab treatment (targeting VEGF pathway) of patients with a variety of solid tumors [START_REF] Dienstmann | Toxicity as a biomarker of efficacy of molecular targeted therapies: focus on EGFR and VEGF inhibiting anticancer drugs[END_REF] was associated with a significant increased risk of developing raised blood pressure (grade 1-2, 25%; grade 3-4, 10%) [START_REF] Geiger-Gritsch | Safety of bevacizumab in patients with advanced cancer: a meta-analysis of randomized controlled trials[END_REF][START_REF] An | Incidence and risk of significantly raised blood pressure in cancer patients treated with bevacizumab: an updated metaanalysis[END_REF]. The results also suggest that significant rise in blood pressure was associated with bevacizumab was dose-dependent. Indeed, high-dose of bevacizumab caused high blood pressure. In addition, increased blood pressure with high dose of bevacizumab was observed in patients with RCC and breast cancer, but not in patients with NSCLC, CRC and pancreatic cancer [START_REF] An | Incidence and risk of significantly raised blood pressure in cancer patients treated with bevacizumab: an updated metaanalysis[END_REF]. Although in this later work the involvement of NO in the raise of blood pressure was not investigated, other kinase inhibitors of the VEGF signaling pathway have also shown a NO-dependent increase in blood pressure. It is the case of pazopanib and sunitinib in the treatment of advanced RCC in which it was shown that pazopanib-treatment was associated with hypertension and decreased urine and plasma nitrite/nitrate, the stable NO-metabolites [START_REF] Tinning | Pazopanib-Induced Hypertension in Patients With Renal Cell Carcinoma Is Associated With Low Urine Excretion of NO Metabolites[END_REF]. Similarly, the urine nitrate concentration was lower in sunitinibtreated patients that developed hypertension [START_REF] Dalbeni | Effects of Antiangiogenetic Drugs on Microcirculation and Macrocirculation in Patients with Advanced-Stage Renal Cancer[END_REF]. It is also the case of lenvatinib and regorafenib, targeting the VEGF signaling pathway, which showed an increase in blood pressure that it was associated with a decrease of NO in sera of differentiated thyroid carcinoma [START_REF] Sueta | Lenvatinib, an oral multi-kinases inhibitor, -associated hypertension: Potential role of vascular endothelial dysfunction[END_REF] and in GISTs [START_REF] De Jesus-Gonzalez | Regorafenib induces rapid and reversible changes in plasma nitric oxide and endothelin-1[END_REF].

Regulatory impact of NO on protein kinases a. NO as a protein kinase activator

Several reports have demonstrated that the intracellular production of NO by NOS is required for the phosphorylation of subsequent activation of EGFR signaling pathways.

It is well known that overexpression of iNOS is significantly associated with tumor growth and angiogenesis, in breast cancer among other cancer types [START_REF] Ekmekcioglu | Inducible nitric oxide synthase and nitrotyrosine in human metastatic melanoma tumors correlate with poor survival[END_REF][START_REF] Vakkala | Inducible nitric oxide synthase expression, apoptosis, and angiogenesis in in situ and invasive breast carcinomas[END_REF]. Indeed, high iNOS expression significantly correlates with EGFR phosphorylation, its activation and poor survival in various breast cancer subtypes [START_REF] Glynn | Increased NOS2 predicts poor survival in estrogen receptor-negative breast cancer patients[END_REF][START_REF] Switzer | S-nitrosylation of EGFR and Src activates an oncogenic signaling network in human basal-like breast cancer[END_REF]. Accordingly, in response to ionizing radiation, endothelial nitric oxide synthase (eNOS) increases NO production and EGFR phosphorylation and activation [START_REF] Lee | Activation of epidermal growth factor receptor and its downstream signaling pathway by nitric oxide in response to ionizing radiation[END_REF]. Another study has showed that eNOS-induced NO can promote EGFR S-nitrosylation and tyrosine residues phosphorylation. Donnini et al., demonstrating that the activation of iNOS/guanylate cyclase (CG) and MAPK-ERK1/2 are required to promote squamous cell carcinoma invasion and growth. This was mediated by EGFR transactivation via prostaglandin E receptor 2 (EP2)/protein kinase A (PKA) and c-Src signaling pathways [START_REF] Donnini | EP2 prostanoid receptor promotes squamous cell carcinoma growth through epidermal growth factor receptor transactivation and iNOS and ERK1/2 pathways[END_REF]. Interestingly, EGFR, in the nucleus, can function as a transcription factor. Indeed the transcriptional activation of iNOS gene can result from the interaction of nuclear EGFR with signal transducer and activator of transcription 3 (STAT3) [START_REF] Lo | Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway[END_REF]. Together, these data indicate a possible feedback loop for the regulation of the EGFR signaling pathways.

NO derived from NO donors can also positively regulate the EGFR signaling pathways.

Upon exposure of triple negative breast cancer cell lines (MDA-MB-468 and HCC1806) to the NO donor DETA/NO an increase in EGFR tyrosine phosphorylation (Y1173 in MDA-MB-468 and Y1173, Y1068 and Y1045 in HCC1806 cells) and subsequent activation were found involved in tumor cell migration and invasion [START_REF] Garrido | Impact of inducible nitric oxide synthase (iNOS) expression on triple negative breast cancer outcome and activation of EGFR and ERK signaling pathways[END_REF].

Another very important tyrosine kinase receptor is VEGFR, which upon binding to its ligand VEGF leads to vasculogenesis and angiogenesis [START_REF] Shibuya | Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti-and Pro-Angiogenic Therapies[END_REF]. VEGF is known to be upregulated by cancer cells generating NO, which contributes to increased neovascularization and tumor metastasis [START_REF] Ambs | p53 and vascular endothelial growth factor regulate tumor growth of NOS2-expressing human carcinoma cells[END_REF]. Furthermore, Nakamura, Y. et al., showed that treatment of breast cancer cells MDA-MB6231 with the NO donor DETA/NONOate, induced an increase in VEGF-C expression and nitrite/nitrate production. All of these changes were correlated with lymph node metastasis [START_REF] Nakamura | Nitric oxide in breast cancer: induction of vascular endothelial growth factor-C and correlation with metastasis and poor prognosis[END_REF].

NO can also positively regulate non-receptor tyrosine kinases as Src and KRAS.

Indeed, NO donors such as DETANO triggered c-Src S-nitrosylation leading to tyrosine kinase activation attested by its phosphorylation at Tyr419 and increased Akt Ser473 and STAT3

Tyr705 phosphorylation [START_REF] Switzer | S-nitrosylation of EGFR and Src activates an oncogenic signaling network in human basal-like breast cancer[END_REF]. Similarly, the NO donor SNP causes S-nitrosylation of c-Src at cysteine 498 to stimulate its kinase activity in fibroblasts. Similar effect was found in breast cancer cells treated with beta-estradiol via iNOS activation [START_REF] Rahman | S-nitrosylation at cysteine 498 of c-Src tyrosine kinase regulates nitric oxide-mediated cell invasion[END_REF]. However iNOS can be targeted by Src. Actually Src induces Tyr1055 iNOS residue phosphorylation [START_REF] Tyryshkin | Src kinase-mediated phosphorylation stabilizes inducible nitric-oxide synthase in normal cells and cancer cells[END_REF]. It is well documented that KRAS is also oncogenic. Its mutation in cancer maintained it in its activated MAP kinase signaling pathway activation [START_REF] Oliveira | The low molecular weight S-nitrosothiol, S-nitroso-N-acetylpenicillamine, promotes cell cycle progression in rabbit aortic endothelial cells[END_REF]. Lopez-Carera et al., investigated the impact of iNOS overexpression observed in melanoma and others cancer cells. They found that iNOS induced mTOR pathway activation in melanoma cells. Mechanistically, the authors showed that iNOS triggered S-nitrosylation of tuberous sclerosis complex (TSC) 2, a driver for the inhibition of dimerization of TSC2 with its inhibitory partner TSC1, increased GTPase activity of its target Ras homolog enriched in brain (Rheb), a key activator of mTOR signaling pathway [START_REF] Lopez-Rivera | Inducible nitric oxide synthase drives mTOR pathway activation and proliferation of human melanoma by reversible nitrosylation of TSC2[END_REF]. NO could also activate the mTOR signaling pathway indirectly. Indeed, Zhu et al., showed that neuronal NOS (nNOS) S-nitrosylates the phosphatase and tensin homolog (PTEN) protein resulting to Akt/mTOR signaling activation, reducing autophagy and promoting the survival of nasopharyngeal carcinoma cells [START_REF] Zhu | NOS1[END_REF].

b. NO as a protein kinase inhibitor

In agreement with the well-documented ambivalent role of NO in cancer, various studies have reported a negative regulatory effect of NO on protein kinases. Indeed, NO can inhibit pathways involved in the proliferation and survival of cancer cells via its potential to downregulate the activity of several protein kinases. Some of these protein kinases are the target of selective PKIs currently undergoing clinical trials.

The S-nitrosylation of EGFR cysteine residues at position 166 and 305 leads to its inactivation in fibroblast and neuroblastoma cells, respectively [START_REF] Estrada | Nitric oxide reversibly inhibits the epidermal growth factor receptor tyrosine kinase[END_REF][START_REF] Murillo-Carretero | S-Nitrosylation of the epidermal growth factor receptor: a regulatory mechanism of receptor tyrosine kinase activity[END_REF]. Ruano et al., also demonstrated that NO-mediated inhibition of human epidermoid carcinoma cells was correlated with the inhibition of EGFR tyrosine phosphorylation and the induction of a tyrosine phosphorylation of a nitric oxide-induced 58-kDa phosphoprotein (NOIPP-58), only in the presence of EGF [START_REF] Ruano | Nitric oxide-induced epidermal growth factor-dependent phosphorylations in A431 tumour cells[END_REF]. Accordingly, but in another context, tyrosine nitration of EGFR, caused by NO derived from iNOS, induces a decrease in tyrosine phosphorylation and an inhibition of neural stem cell proliferation [START_REF] Carreira | Nitric oxide from inflammatory origin impairs neural stem cell proliferation by inhibiting epidermal growth factor receptor signaling[END_REF].

In addition, the MEK family proteins ERK1/2 that are targeted by tramatenib and cobimetinib in the treatment of BRAF mutated metastatic melanoma, are S-nitrosylated by NO. Indeed, NO donors SNP or GSNO led to increase in ERK1/2 S-nitrosylation at cysteine residue 183, and a reduction of ERK1/2 phosphorylation that can trigger cell growth inhibition and apoptosis of cancer cells [START_REF] Feng | S-nitrosylation of ERK inhibits ERK phosphorylation and induces apoptosis[END_REF][START_REF] Jin | Effects of ERK1/2 Snitrosylation on ERK1/2 phosphorylation and cell survival in glioma cells[END_REF]. Similarly, S-nitrosylated Akt (cysteine residue 224) [START_REF] Yasukawa | S-nitrosylation-dependent inactivation of Akt/protein kinase B in insulin resistance[END_REF] and nitrated Janus kinase-2 (JAK2) (tyrosine residues 1007 and 1008) [START_REF] Elsasser | Caveolae nitration of Janus kinase-2 at the 1007Y-1008Y site: coordinating inflammatory response and metabolic hormone readjustment within the somatotropic axis[END_REF] can negatively control both oncogenic PI3K/Akt and JAK2/STAT signaling pathways.

These oncogenic pathways in various types of cancer are targeted by selective inhibitory molecules. Idelalisib and copenlalisip (PI3K inhibitors) in the treatment of chronic lymphoid leukemia (CLL), non-Hodgkin lymphoma (NHL), follicular lymphoma (FL) and ruxolitinib (JAK2 inhibitor) in the treatment of myelofibrosis [START_REF] Moldogazieva | Reactive Oxygen and Nitrogen Species-Induced Protein Modifications: Implication in Carcinogenesis and Anticancer Therapy[END_REF]. Several other protein kinases including STAT3, JNK and IKKβ involved in growth factors or cytokine-mediated signaling pathways are also targeted by NO. STAT3, a key partner of JAK2 in IL-6 mediated signaling pathways, was inhibited by S-nitrosylation at cysteine residue 259 by the NO donor (GSNO) or through iNOS activation. This was associated with decreased cancer cell proliferation and increased apoptosis [START_REF] Singh | STAT3 Regulation By S-Nitrosylation: Implication In Cancer[END_REF][START_REF] Kaliyaperumal | S-nitrosoglutathione-mediated STAT3 regulation in efficacy of radiotherapy and cisplatin therapy in head and neck squamous cell carcinoma[END_REF]. Also, JNK proteins (JNK1, 2, 3) are S-nitrosylated upon NO generation via interferon gamma (IFNγ)-induced iNOS or the NO-donor SNAP in murine microglial cells thus suppressing their interaction and kinase activity [START_REF] Plenchette | S-Nitrosylation in TNF superfamily signaling pathway: Implication in cancer[END_REF]. Finally, the IKKβ kinase activity was also repressed by S-nitrosylation (Cysteine 179). Such effect caused inhibition of the enzymatic activity of this kinase preventing the activation of an essential cell survival pathway, the classical NF-kB pathway [START_REF] Reynaert | Nitric oxide represses inhibitory kappaB kinase through S-nitrosylation[END_REF][START_REF] Yakovlev | Tyrosine nitration of IkappaBalpha: a novel mechanism for NF-kappaB activation[END_REF].

c. Effect of NO on PKIs-mediated cell death

In addition to the different relationships between NO and kinase inhibitors mentioned above, NO can synergize with certain kinase inhibitors to induce death or inhibit the proliferation of cancer cells. Studies have shown that two EGFR signaling pathway inhibitors erlotinib and ZD1839 synergized with NO donors, NO-aspirin and SNP, to induced antiproliferative effect or cell death in several lung and prostatic cancer cell lines, respectively [START_REF] Song | Nitric oxide-donating aspirin (NO-Aspirin) suppresses lung tumorigenesis in vitro and in vivo and these effects are associated with modulation of the EGFR signaling pathway[END_REF][START_REF] Mimeault | Synergistic antiproliferative and apoptotic effects induced by mixed epidermal growth factor receptor inhibitor ZD1839 and nitric oxide donor in human prostatic cancer cell lines[END_REF].

A synergistic effect, between PKIs and NO in promoting cancer cell death, has been also observed with other PKIs currently undergoing preclinical studies. Indeed, H89 (N-[2bromocinnamylamino)ethyl]-5-isoquinolinesulfonammide) is a small molecule that has always been known as PKA inhibitor [START_REF] Chijiwa | Inhibition of forskolin-induced neurite outgrowth and protein phosphorylation by a newly synthesized selective inhibitor of cyclic AMP-dependent protein kinase, N-[2-(pbromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), of PC12D pheochromocytoma cells[END_REF]. Although Davies and collaborators showed that H89 is able to inhibit at least 8 other kinases, such as MSK1, S6K1, ROCK II, AMPK, CHK1, KBα, MAPKAP-K1b and SGK [START_REF] Davies | Specificity and mechanism of action of some commonly used protein kinase inhibitors[END_REF]. H89 structure is similar to ATP, so this small molecule is able to inhibit kinases activity competitively with ATP [START_REF] Hidaka | Molecular pharmacology of protein kinases[END_REF]. Some studies used H89 to assess the role of PKA in different tissues in vitro, such as heart muscle, liver, smooth muscle, epithelial cells and neuronal tissue [START_REF] Ferro | Nitric oxide-dependent beta2adrenergic dilatation of rat aorta is mediated through activation of both protein kinase A and Akt[END_REF][START_REF] Fassett | Type I collagen structure regulates cell morphology and EGF signaling in primary rat hepatocytes through cAMP-dependent protein kinase A[END_REF][START_REF] Robinet | PI 3-kinase, protein kinase C, and protein kinase A are involved in the trigger phase of beta1-adrenergic preconditioning[END_REF][START_REF] Burvall | Expression of TNFalpha and its receptors R1 and R2 in human alveolar epithelial cells exposed to organic dust and the effects of 8-bromo-cAMP and protein kinase A modulation[END_REF][START_REF] Kaneishi | 3',5'-cyclic adenosine monophosphate augments intracellular Ca2+ concentration and gonadotropin-releasing hormone (GnRH) release in immortalized GnRH neurons in an Na+ -dependent manner[END_REF]. Moreover, H89 also has an activity in vivo as an anti-inflammatory strategy to treat inflammation in mice [START_REF] Reber | The AGC kinase inhibitor H89 attenuates airway inflammation in mouse models of asthma[END_REF]. Unfortunately, the role of H89 in cancer is not well established. Recent studies have shown that H89 is able to enhance tetrandrine (a bisbenzylisoquinoline alkaloid) and HA22 (moxetumomab pasudotox) effect on human cancer cells in vitro and in vivo [START_REF] Yu | Combination therapy with protein kinase inhibitor H89 and Tetrandrine elicits enhanced synergistic antitumor efficacy[END_REF][START_REF] Liu | Protein Kinase Inhibitor H89 Enhances the Activity of Pseudomonas Exotoxin A-Based Immunotoxins[END_REF]. Recently, Li and coworkers showed that H89 is able to improve the activity of the oncolytic virus M1 to induce tumor regression in various cancer cells [START_REF] Li | A classical PKA inhibitor increases the oncolytic effect of M1 virus via activation of exchange protein directly activated by cAMP 1[END_REF]. The relationship between H89 and NO is not clearly understood.

The anti-tumor effect of the NO-donor nitroglycerin (NTG) is well established in various cancer types. Some studies have shown that the combination of H89 and NTG enhances cell death in colon cancer cells. Indeed, H89 induces reactive oxygen species (ROS) production which combined with NO, triggers apoptotic cell death by caspase activation [START_REF] Cortier | H89 enhances the sensitivity of cancer cells to glyceryl trinitrate through a purinergic receptor-dependent pathway[END_REF]. Even if H89 is primarily known for kinases inhibition, Boina-Ali and coworkers showed that the molecule induces an unexpected Akt activation. In fact, Akt activation induced by H89 sensitizes colon cancer cells to death induced by NTG and triciribine (an Akt inhibitor) [START_REF] Boina-Ali | Activation of Akt by mamma lian target rapamycin complex 2 renders colon cancer cells sensitive to apoptisis induced by nitric oxide and Akt inhibitor[END_REF].

IV. PKIs and NO donors: towards potential combinatory treatments?

Over the last two decades, the clinical development and approval of a growing Indeed, the difficulty to circumvent protein kinase mutational resistance is well exemplified by EAI045, a fourth-generation EGFR PKI under current preclinical investigation [START_REF] Wang | EAI045: The fourth-generation EGFR inhibitor overcoming T790M and C797S resistance[END_REF].

Although EAI045 seems to unveil encouraging results in terms of overcoming resistance to the third-generation EGFR PKI in advanced NSCLC models, clinical trials with EAI045 have not been conducted yet. In the era of precision medicine, the design and development of novel generation of PKIs is a perpetual challenge in an attempt to maximize clinical benefit.

The second approach consists in combining PKIs with chemotherapeutic agents.

Major success on combination therapies has been realized in cancer but the design of more in NSCLC patients [START_REF] Liu | VEGFR-TKIs combined with chemotherapy for advanced non-small cell lung cancer: A systematic review[END_REF]. However, whether the combinations of either VEGFR-PKIs or EGFR-PKIs with various chemotherapeutic agents present higher efficiency than with PKIs alone in advanced NSCLC remain controversial [START_REF] Reck | Beyond the TRIBUTE trial: integrating HER1/EGFR tyrosine kinase inhibitors with chemotherapy in advanced NSCLC[END_REF][START_REF] Wen | Combination of EGFR-TKIs with chemotherapy versus chemotherapy or EGFR-TKIs alone in advanced NSCLC patients with EGFR mutation[END_REF][START_REF] Scagliotti | Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer[END_REF]. From a molecular perspective, one possible explanation may in part account for p53 mutational status. TP53 tumor suppressor gene is the most frequently mutated genes in cancers. It is well documented that p53 is associated with resistance to many chemotherapeutic agents [START_REF] Muller | p53 mutations in cancer[END_REF]. Because of high frequency p53 mutations in tumors, the activation of alternative cell death pathways in a p53-independent manner, such as apoptosis promoted by cytokines of the Tumor Necrosis Factor (TNF) family, should be considered. A growing number of studies have demonstrated sensitizing effect of NO to tumor-necrosis-factor related apoptosis inducing ligand (TRAIL) [START_REF] Tang | Nitrosylcobalamin promotes cell death via S nitrosylation of Apo2L/TRAIL receptor DR4[END_REF], Fas Ligand (FasL) [START_REF] Leon-Bollotte | S-nitrosylation of the death receptor fas promotes fas ligand-mediated apoptosis in cancer cells[END_REF], and TNFα [START_REF] Romagny | S-Nitrosylation of cIAP1 Switches Cancer Cell Fate from TNFα/TNFR1-Mediated Cell Survival to Cell Death[END_REF] mediated apoptosis in cancer cells. A limited number of proteins modified by either S-nitrosylation or nitration processes are known to drive cell death pathways (for review [START_REF] Plenchette | NO and cancer: itinerary of a double agent[END_REF]).

Interestingly, a substantial body of evidences indicates that NO-based treatment (particularly via NO donors) could potentially contribute to overcome resistance to PKIs in cancer patients.

It is now well recognized that NO-mediated post-translational modifications influence cell signaling in a similar extent as for phosphorylation or other major post-translation modification such as ubiquitination [START_REF] Hess | Regulation by S-nitrosylation of protein post-translational modification[END_REF]. S-nitrosylation is a critical regulator of phosphorylation, ubiquitination or acetylation for example. S-nitrosylation is also an important regulatory mechanism of several protein kinases and subsequent posttranslational modification by phosphorylation. Even though protein post-translation modification by S-nitrosylation can either activate or inhibit enzymatic activities, Snitrosylated protein kinases are most likely inhibited [START_REF] Hess | Regulation by S-nitrosylation of protein post-translational modification[END_REF]. NO can alter protein kinase activity not only by S-nitrosylation of the cysteine residue in its catalytic domain, but also by preventing the binding to its downstream target. Consistently, tyrosine nitration can also change the function of key proteins involved in cellular signaling events. Phosphorylation and nitration can occur within the same tyrosine residue. Since tyrosine nitration rather inhibits than activate the function of proteins, tyrosine nitration may cooperate with PKIs to efficiently prevent phosphorylation events and downstream signaling pathways that control cancer cell growth. Thus, NO have the added benefit to act not only as a multi-targeted kinase inhibitor but also as inhibitor of numerous protein substrates which is of particular interest to overcome PKI resistance-mediated activation of redundant and alternative signaling pathways.

Recent preclinical reports currently abound for the development of NO donors to overcome primary or acquired resistance to PKIs. For example, NO donor/natural product hybrids represent a promising anticancer strategy to potentiate different PKIs anti-cancer properties. Indeed, an oleanolic acid/hederagenin-NO donor hybrid has demonstrated potent cytotoxicity against gefitinib-resistant (EGFR-L858R/T790M mutations) and osimertinib-resistant (EGFR-L858R/T790M/C797S mutations) NSCLC cancer cells. This novel NO-donor hybrid represents a potent compound to overcome frequent EGFR-PKI resistance in NSCLC lung cancer [START_REF] Chen | Discovery of an Oleanolic Acid/Hederagenin-Nitric Oxide Donor Hybrid as an EGFR Tyrosine Kinase Inhibitor for Non-Small-Cell Lung Cancer[END_REF]. The design of a dual-functional inhibitor NO donor/selective STAT3 inhibitor ((NO)-releasing quinolone-1,2,4-triazole/oxime hybrid) significantly improved the cytotoxicity of melanoma cell lines with BRAF-V600E mutant and resistant to BRAF inhibitors [START_REF] Kaoud | NO-releasing STAT3 inhibitors suppress BRAF-mutant melanoma growth[END_REF]. Interestingly, in a previous report, a series of NO donor/EGFR inhibitors (phenylsulfonyfuroxan-based anilinopyrimidines) harbouring a strong activity against EGFR T790M mutant, had yet demonstrated EGFR kinase inhibitory and antiproliferative potential against EGFR mutated NSCLC cell lines [START_REF] Han | Nitric oxide donating anilinopyrimidines: synthesis and biological evaluation as EGFR inhibitors[END_REF].

The treatment of the Bcr-Abl + CML cell line K562 with the NO donor sodium nitroprusside have shown to enhance imatinib-mediated apoptosis [START_REF] Rakshit | N-acetyl cysteine enhances imatinib-induced apoptosis of Bcr-Abl+ cells by endothelial nitric oxide synthase-mediated production of nitric oxide[END_REF]. Moreover, NAC mediated-scavenging of ROS in Bcr-Abl + CML cell lines and primary cells from CML patients (imatinib-resistant and imatinib-sensitive cells) co-treated with imatinib are correlated with enhanced production of NO and subsequent NO-dependent cell death [START_REF] Rakshit | N-acetyl cysteine enhances imatinib-induced apoptosis of Bcr-Abl+ cells by endothelial nitric oxide synthase-mediated production of nitric oxide[END_REF].

Vemurafenib-mediated growth inhibition of the BRAF-V600E melanoma cell line A375

has been shown to be dependent on the production of the superoxide anion O2 .-and NO [START_REF] Hao | Melatonin synergizes BRAF-targeting agent vemurafenib in melanoma treatment by inhibiting iNOS/hTERT signaling and cancer-stem cell traits[END_REF]. These results suggest a peroxynitrite-dependent cytotoxicity involving protein tyrosine nitration. Thus, NO appears as a key factor for PKI efficacy which sustains the rationale for the development of novel combination therapies PKI/NO donor.

Preclinical studies demonstrated that vemurafenib-mediated antitumor activities can be enhanced by abrogating nucleus translocation of NF-kB p50/p65 [START_REF] Hao | Melatonin synergizes BRAF-targeting agent vemurafenib in melanoma treatment by inhibiting iNOS/hTERT signaling and cancer-stem cell traits[END_REF]. On the other hand, NO (either endogenously produced or released by NO donors) can inhibit the activation of the NF-kB pathway through the S-nitrosylation of IKKβ, p50, p65 and cellular inhibitor of apoptosis protein 1 (cIAP1) [START_REF] Reynaert | Nitric oxide represses inhibitory kappaB kinase through S-nitrosylation[END_REF][START_REF] Romagny | S-Nitrosylation of cIAP1 Switches Cancer Cell Fate from TNFα/TNFR1-Mediated Cell Survival to Cell Death[END_REF][START_REF] Colasanti | Nitric oxide: an inhibitor of NF-kappaB/Rel system in glial cells[END_REF][START_REF] Marshall | Inhibition of NF-kappa B by S-nitrosylation[END_REF][START_REF] Chattopadhyay | NO-releasing NSAIDs suppress NF-κB signaling in vitro and in vivo through S-nitrosylation[END_REF].

Concluding remarks

The mode of action of both PKIs and NO-based protein post-translational modifications revealed functional overlaps for some oncogenic targets underlying an interest in PKIs and NO donors combination in cancer therapy. In this context, the effect of NO (Snitrosylation or nitration) could possibly overcome PKI resistance. Whether it acts through a direct or indirect way, NO may exert a regulatory control over protein kinases involved in important cancer signaling pathways as observed with PKIs.

A growing number of clinical studies have evaluated the NO donor NTG as an anticancer drug in combination with either radiotherapy or chemotherapy agents. The majority of clinical studies were conducted in patients with NSCLC. The results obtained for the first phase II trial demonstrated clinical benefit (improved overall survival) for patients treated with the combination therapy NTG/vinorelbine and cisplatin [START_REF] Yasuda | Indoleamine 2,3-dioxygenase 1 : Ido1 Inductible nitric oxide synthase: iNOS Interleukin: IL Janus kinase 2: JAK2 Macrophage 1/2 phenotype: M1/M2 Mammalian target of rapamycin: mTOR MET proto-oncogene receptor tyrosine kinase: MET Mitogen-activated protein kinase: MAPK Mitogen extracellular kinases: MEK Micro RNA: miRNA Myeloid-derived suppressor cells: MDSC (N-[2-bromocinnamylamino)ethyl]-5-isoquinolinesulfonammide): H89 Neuronal nitric oxide synthase: nNOS Nitric[END_REF].

New combinatorial treatments, designed with PKIs currently approved by the FDA and NO donors (such as NTG), have never been explored yet. Studies are needed to determine whether the use of NO donors would enhance the effectiveness of PKIs in cancer treatment.

  inductible nitric oxide synthase (iNOS) expression and NO production in glioma-activated microglia cells (involved in central nervous system (CNS) cancers) to express a macrophage 1 (M1) phenotype (antitumoral). In parallel, rapamycin and RAD001 prevented the acquisition of a M2 phenotype (protumoral) by reducing both arginase and interleukin (IL)-10 gene expression, possibly resulting in antitumor action[START_REF] Lisi | The mTOR kinase inhibitors polarize gliomaactivated microglia to express a M1 phenotype[END_REF]. Another study reported that ibrutinib, an inhibitor of BTK and IL-2-inducible T-cell kinase, clinically used for the treatment of B-cell malignancies, modulates myeloid-derived suppressor cells (MDSC) function and generation. This inhibitory function is associated with ibrutinib-impaired iNOS and arginase 1 expression in MDSC cells (a hallmark for MDSC exhaustion) while indoleamine 2,3dioxygenase 1 (IDO1) trended towards increased expression, revealing a potential strategy for enhancing immune-bases therapy in cancer[START_REF] Stiff | Myeloid-Derived Suppressor Cells Express Bruton's Tyrosine Kinase and Can Be Depleted in Tumor-Bearing Hosts by Ibrutinib Treatment[END_REF]. Similarly, axitinib, a selective inhibitor of VEGFR tyrosine kinases, indicated in the treatment of patients with advanced renal cell carcinoma after failure of previous treatment with sunitinib or cytokine, induced the same effect as ibrutinib. Indeed, axitinib suppressed the lung metastasis of melanoma cells, prolonged survival of tumor-bearing mice and reduced the proportion of MDSC.

  status. KRAS activation could occur through other mechanisms. Studies showed that eNOS induces the S-nitrosylation of cysteine at position 118 and activation of wild-type Ras protein leading to the stimulation of PI3K/Akt signaling, thus promoting tumor growth[START_REF] Lim | Tumour maintenance is mediated by eNOS[END_REF]. The same year, Oliveira et al., found that, in rabbit aortic endothelial cells, low concentrations of S-Nitrosothiols/NO (RSNO/NO) induced Ras S-nitrosylation and consequently Ras-ERK1/2

  number of novel PKIs have tremendously improved the landscape of targeted therapies to treat cancer. Despite significant clinical benefits (improvement in OS and PFS) observed for some patients, persistent tumor intrinsic resistance or acquired resistance to PKIs are still a limitation of treatment. How to make the best use of PKIs to treat cancer patients remains an open question. To this end, better knowledge of the molecular mechanisms of resistance currently represents an intensive area of research to achieve durable efficacy.As a hallmark of cancer cell development, novel mutations mediating resistance toPKIs occurs inevitably and rapidly with the emergence of resistant tumor clones. A first strategy consisted in developing the so called "next-generation" PKIs in order to improve over and over again their potency and selectivity toward specific newly mutated kinases.

  personalized treatment is needed PKIs are signaling therapeutic agents designed to mainly target some of the fundamental hallmarks of cancer i.e. cell proliferation, cell survival and tumor angiogenesis. Various clinical trials studying combinatorial strategies of such cytostatic agents with cytotoxic agents like chemotherapeutic drugs (soliciting other hallmarks of cancer) have been focused on NSCLC patients. Many clinical trials have demonstrated the clinical benefit of certain VEGFR-PKIs when combined with chemotherapy

Figure 1 .

 1 Figure 1. Impact of NO on protein kinases and PKIs activities. Summary of the ambivalent impact of NO toward PKI (either promoting or inhibiting PKI's antitumoral potential) and protein kinases function (regulated at the transcriptional or the post-translational level by NO).

Acknowledgements

The authors acknowledge the financial support from « Région Bourgogne », « La Ligue Contre le Cancer (Conférence de coordination Interrégionale Est) » and « Qatar Foundation ».