Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) resistance in metastatic renal cell carcinoma (mRCC): Possible mechanisms and clinical approaches
Introduction: The approvals of sorafenib, sunitinib, and pazopanib have led to increased options for patients with mRCC. Unfortunately, some patients treated with these vascular endothelial growth factor receptor (VEGFR) TKI progress rapidly, while the majority of remaining patients will develop evidence of disease progression within 2 years. Objectives: We gathered preclinical and clinical evidence regarding potential mechanisms of VEGFR TKI resistance and clinical approaches to counter it. Methods: We searched the published medical literature, searching the National Library of Medicine (PubMed) as well as abstracts from annual meetings of the American Society of Clinical Oncology (ASCO) and American Association for Cancer Research (AACR). Results: No clear evidence-based mechanism of VEGFR TKI resistance has been defined to date; therefore, we summarize the existing hypothesisgenerating preclinical, biomarker, and clinical data. Potential mechanisms of resistance to VEGFR TKI include variations in the inherent genetic alterations associated with RCC, independent of VHL. In addition, response to hypoxia induced by VEGFR TKI may drive alternative growth factor mediated angiogenesis. Molecular imaging evidence of early angiogenesis and proliferation rebound following VEGFR TKI exposure suggests progression is still driven by a proangiogenic phenotype. Conclusion: By necessity, clinicians must currently make treatment decisions on the basis of limited data regarding the biology of VEGFR TKI resistance. RCC is a heterogeneous disease from the onset. Understanding the specific genetic profiles of sensitive and resistant subtypes of RCC may aid in both first-line and subsequent treatment selection. In addition, better understanding of tumor response and resistance may lead to novel combination strategies in the future.
