Abstract
Sunitinib, a multityrosine kinase inhibitor, is currently the standard first-line therapy in metastatic renal cell carcinoma (mRCC) and is also used in treating patients with pancreatic neuroendocrine and imatinib-resistant gastrointestinal stromal tumors (GIST). Nevertheless, most patients eventually relapse secondary to intrinsic or acquired sunitinib resistance. Autophagy has been reported to contribute to both chemo-sensitivity and -resistance. However, over the last few years, controversial regulatory effects of sunitinib on autophagy have been reported. Since gaining insights into the underlying molecular insights and clinical implications is indispensible for achieving optimum therapeutic response, this minireview article sheds light on the role of a network of prosurvival signaling pathways recently identified as key mediators of sunitinib resistance with established and emerging functions as autophagy regulators. Furthermore, we underscore putative prognostic biomarkers of sunitinib responsiveness that could guide clinicians toward patient stratification and more individualized therapy. Importantly, innovative therapeutic strategies/approaches to overcome sunitinib resistance both evaluated in preclinical studies and perspective clinical trials are discussed which could ultimately be translated to better clinical outcome.
Highlights
Following the initial breakthrough success of imatinib, the first FDA-approved tyrosine kinase inhibitor(TKI), TKIs were deemed to revolutionize cancer therapy
Emergence of imatinib-resistance prompted development of novel structurally distinct TKIs (Abdel-Aziz et al, 2015; Aziz et al, 2016). Among these second-generation TKIs, sunitinib, was designed as an oral small molecule ATP mimetic which competes with endogenous ATP for binding at the catalytic site of several tyrosine kinase receptors including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), fms-like tyrosine kinase-3 receptor (FLT3) and stem cell factor receptor (c-kit) which are preferentially overexpressed in diverse types of cancer (Cella et al, 2015)
In 2006, sunitinib became the first drug jointly approved by the FDA for treating both metastatic renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor(GIST) patients
Summary
Following the initial breakthrough success of imatinib, the first FDA-approved tyrosine kinase inhibitor(TKI), TKIs were deemed to revolutionize cancer therapy. Emergence of imatinib-resistance prompted development of novel structurally distinct TKIs (Abdel-Aziz et al, 2015; Aziz et al, 2016). Among these second-generation TKIs, sunitinib, was designed as an oral small molecule ATP mimetic which competes with endogenous ATP for binding at the catalytic site of several tyrosine kinase receptors including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), fms-like tyrosine kinase-3 receptor (FLT3) and stem cell factor receptor (c-kit) which are preferentially overexpressed in diverse types of cancer (Cella et al, 2015). Other than mutation or amplification of drug targets, activation of prosurvival signaling pathways is a frequently exploited strategy by cancer cells to evade cell death and sustain their proliferation (Hammers et al, 2010; Shojaei et al, 2010)
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