Identification of mutations associated with acquired resistance to sunitinib in renal cell cancer.

Sunitinib is one of the most widely used targeted therapeutics for renal cell carcinoma (RCC), but acquired resistance against targeted therapies remains a major clinical challenge. To dissect mechanisms of acquired resistance and unravel reliable predictive biomarkers for sunitinib in RCC, we sequenced the exons of 409 tumor‐suppressor genes and oncogenes in paired tumor samples from an RCC patient, obtained at baseline and after development of acquired resistance to sunitinib. From newly arising mutations, we selected, using in silico prediction models, six predicted to be deleterious, located in G6PD, LRP1B, SETD2, TET2, SYNE1, and DCC. Consistently, immunoblotting analysis of lysates derived from sunitinib‐desensitized RCC cells and their parental counterparts showed marked differences in the levels and expression pattern of the proteins encoded by these genes. Our further analysis demonstrates essential roles for these proteins in mediating sunitinib cytotoxicity and shows that their loss of function renders tumor cells resistant to sunitinib in vitro and in vivo. Finally, sunitinib resistance induced by continuous exposure or by inhibition of the six proteins was overcome by treatment with cabozantinib or a low‐dose combination of lenvatinib and everolimus. Collectively, our results unravel novel markers of acquired resistance to sunitinib and clinically relevant approaches for overcoming this resistance in RCC. What's new? Sunitinib, a tyrosine kinase inhibitor, is one of the most commonly used targeted therapeutics for treatment of metastatic renal cell carcinoma (mRCC). However, the majority of patients who initially respond eventually develop acquired resistance. In the present study, by analyzing sequential tumor biopsies from an mRCC patient who developed acquired resistance to sunitinib, the authors identified mutations in genes whose loss of function conferred sunitinib resistance to tumor cell lines and xenografted mice and went on to identify critical downstream action mechanisms. The findings may be relevant for the development of predictive biomarkers and new therapeutic strategies in mRCC. [ABSTRACT FROM AUTHOR]