Sunitinib is one of the most widely used targeted therapeutics for renal cell-cancer (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 renal cell-cancer (RCC), we sequenced the exons of 409 tumor-suppressor genes and oncogenes in paired tumor samples from an RCC patient, obtained at baseline and following development of acquired resistance to sunitinib. From newly arising mutations, we selected, using in-silico prediction models, 6 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 render tumor cells resistant to sunitinib in vitro and in vivo. Finally, sunitinib resistance induced by continuous exposure or by inhibition of the 6 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. This article is protected by copyright. All rights reserved.
International journal of cancer. 2019 Mar 08 [Epub ahead of print]
Mohamed Elgendy, Juan Pablo Fusco, Victor Segura, Maria Dolores Lozano, Saverio Minucci, Jose Ignacio Echeveste, Alfonso Gurpide, Mapi Andueza, Ignacio Melero, Miguel F Sanmamed, Maria Rodriguez Ruiz, Alfonso Calvo, Juan Ignacio Pascual, Jose María Velis, Bernardino Miñana, Ricardo Diez Valle, Ruben Pio, Jackeline Agorreta, Marta Abengozar, Maurizio Colecchia, Silvia Brich, Salvatore Lorenzo Renne, Elisabet Guruceaga, Ana Patiño-García, Jose Luis Perez-Gracia
Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy., Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain., IDISNA and Bioinformatics Unit, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain., Health Research Institute of Navarra (IDISNA), Pamplona, Spain., Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.