Synergistic Interaction Between Sunitinib And Docetaxel Is Sequence Dependent In Human Non-small Cell Lung Cancer With EGFR TKIs-resistant Mutation

Background Lung cancer is a life-threatening disease and world health issue,accounting for the majority of all cancer-related deaths. Of all lung cancer cases,non-small cell lung cancer (NSCLC) accounts for approximately80-85%.Unfortunately, the majority of patients present with progressed disease at the time ofdiagnosis. For those patients, drug therapy is an important means of treatment foradvanced NSCLC. Gefitinib and erlotinib are small-molecule epidermal growth factorreceptor (EGFR) tyrosine kinase inhibitors (TKIs) that improve the survival of NSCLCpatients by antagonizing crucial signaling pathways involved in lung cancer growthand malignant progression. It has been shown that the apparent response rates of EGFRTKIs are correlated with the occurrence of activating mutations in the EGFR gene.Nevertheless, patients with EGFR-activating mutations are estimated to account forapproximately only10-30%of all NSCLC cases. The presence of a K-ras or an EGFRT790M mutation is associated with resistance to EGFR-TKIs. The novelsmall-molecule sunitinib malate is an orally administered selective multi-targetedreceptor tyrosine kinase (RTK) inhibitor that inhibits several growth factor receptorsincluding vascular endothelial growth factor receptors (VEGFR1/2/3), platelet-derivedgrowth factor receptors (PDGFRa and PDGFRb), stem cell factor receptor (c-kit), andglial cell-line-derived neurotrophic factor receptor (RET). Sunitinib directly displaysits anti-tumor activity by inhibiting signaling pathways driving proliferation andsurvival mediated by the VEGF, PDGF, and c-kit receptors but may also suppress VEGFR and PDGFR to block angiogenesis, thereby indirectly inhibiting tumor growth.Preclinical and clinical studies have confirmed the anti-tumor activity of this moleculein various types of tumors and cancers. At present, sequential administration isconsidered to be a promising therapeutic approach and has been explored betweenEGFR TKIs and chemotherapy in NSCLC. Therefore, it is worth exploring sequentialadministration of sunitinib and chemotherapy in NSCLC with EGFR T790M or K-rasmutation.Objective Previous studies have demonstrated that sunitinib has the antitumor activityin human non-small cell lung cancer (NSCLC). This study was aimed to investigate theefficacy of single use of sunitinib and that of concurrent or sequential administration ofsunitinib and docetaxel in NSCLC cell lines that are resistant to EGFR TKIs.Methods NSCLC cell lines with EGFR T790M mutation and K-ras mutation wereexposed to either sunitinib or docetaxel or both based on various sequentialadministrations. After exposure, the cell viability was measured by MTT assay, cellcycle distribution was analyzed by flow cytometry and alterations in signaling pathwaywere determined by Western Blot.Results Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell linesand arrested cell cycle at G1Phase whereas docetaxel arrested at S phase. Althoughsingle or concurrent use of sunitinib and docetaxel has some antiproliferative effects,the sequential administrations of both drugs remarkably enhanced anti-tumor activity.When cells were exposed to docetaxel followed by sunitinib, synergism was observed.The molecular basis of this synergism is that the signaling pathways that were initiallyactivated by docetaxel exposure were efficiently suppressed by the subsequent exposureto sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest.Conclusions We demonstrated that in vitro single agent sunitinib andschedule-dependent growth inhibition in combination sunitinib with docetaxel. Wefound that sunitinib significant growth inhibition in EGFR TKIs-resistant NSCLC cells.In addition, the sequential administration of docetaxel followed by sunitinib was anoptimum schedule against NSCLC regardless of the mutation status of EGFR and K-ras.Based on these findings, it is worth investigating the possibility for the clinicalapplication of sunitinib as a single targeted therapy or as part of a sequentialadministration schedule in combination with conventional cytotoxic chemotherapydrugs for patients with EGFR TKIs-resistant NSCLC. Whereas, IC50value of singleagent sunitinib in vitro was found to be significantly higher than plasma concentrationsin vivo, further studies are needed to explore in vivo sunitinib as a single agent and theschedule-dependent administration of sunitinib plus docetaxel in EGFR TKIs-resistantNSCLC.