Identification of mutations associated with acquired resistance to sunitinib in renal cell-cancer
Elgendy M (1,2), Fusco JP (3,4), Segura V (5), Lozano MD (4,6,7), Minucci S (1,8), Echeveste JI (4,6), Gurpide A (3,4), Andueza M (3,4), Melero I (4,7,9), Sanmamed MF (3,4), Ruiz MR (3,4), Calvo A (4,10), Pascual JI (4,11), Velis JM (4,11), Miñana B (4,11), Valle RD (4,12), Pio R (4,7,13), Agorreta J (4,7,13), Abengozar M (4,6), Colecchia M (14), Brich S (14), Renne SL (14), Guruceaga E (5), Patiño-García A (4,13,15), Perez-Gracia JL (3,4,7).
(1) Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
(2) Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria.
(3) Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain.
(4) Health Research Institute of Navarra (IDISNA), Pamplona, Spain.
(5) IDISNA and Bioinformatics Unit, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain.
(6) Pathology Department, Clinica Universidad de Navarra, Pamplona, Spain.
(7) Centro de Investigación Biomédica en Red de Cáncer (CIBERONC).
(8) Department of Biosciences, University of Milan, Milan, Italy.
(9) Department of Immunology, Center for Applied Medical Research (CIMA), Pamplona, Spain.
(10) Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Navarra, Spain.
(11) Department of Urology, Clinica Universidad de Navarra, Pamplona and Madrid, Spain.
(12) Department of Neurosurgery, University Clinic of Navarra, Pamplona, Spain.
(13) Program in Solid Tumors. Center for Applied Medical Research (CIMA), Pamplona, Spain.
(14) Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
(15) Department of Pediatrics and Clinical Genetics, Clinica Universidad de Navarra, Pamplona, Spain.
Magazine: International Journal of Cancer
Date: Mar 8, 2019Immunology [SP] Urology [SP] Pathological Anatomy [SP] Clinical Genetics Unit [SP] Medical Oncology
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.
CITATION Int J Cancer. 2019 Mar 8. doi: 10.1002/ijc.32256.
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