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

Authors
  • Elgendy, Mohamed1, 2
  • Fusco, Juan Pablo3, 4
  • Segura, Victor5
  • Lozano, Maria Dolores4, 6, 7
  • Minucci, Saverio1, 8
  • Echeveste, Jose Ignacio4, 6
  • Gurpide, Alfonso3, 4
  • Andueza, Mapi3, 4
  • Melero, Ignacio4, 7, 9
  • Sanmamed, Miguel F3, 4
  • Ruiz, Maria Rodriguez3, 4
  • Calvo, Alfonso4, 10
  • Pascual, Juan Ignacio4, 11
  • Velis, Jose María4, 11
  • Miñana, Bernardino4, 11
  • Valle, Ricardo Diez4, 12
  • Pio, Ruben4, 7, 13
  • Agorreta, Jackeline4, 7, 13
  • Abengozar, Marta4, 6
  • Colecchia, Maurizio14
  • And 5 more
  • 1 Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy. , (Italy)
  • 2 Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria. , (Austria)
  • 3 Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain. , (Spain)
  • 4 Health Research Institute of Navarra (IDISNA), Pamplona, Spain. , (Spain)
  • 5 Bioinformatics Unit, Center for Applied Medical Research (CIMA), IDISNA, University of Navarra, Pamplona, Spain. , (Spain)
  • 6 Pathology Department, Clinica Universidad de Navarra, Pamplona, Spain. , (Spain)
  • 7 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain. , (Spain)
  • 8 Department of Biosciences, University of Milan, Milan, Italy. , (Italy)
  • 9 Department of Immunology, Center for Applied Medical Research (CIMA), Pamplona, Spain. , (Spain)
  • 10 Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain. , (Spain)
  • 11 Department of Urology, Clinica Universidad de Navarra, Pamplona, Spain. , (Spain)
  • 12 Department of Neurosurgery, University Clinic of Navarra, Pamplona, Spain. , (Spain)
  • 13 Program in Solid Tumors, Center for Applied Medical Research (CIMA), Pamplona, Spain. , (Spain)
  • 14 Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy. , (Italy)
  • 15 Department of Pediatrics and Clinical Genetics, Clinica Universidad de Navarra, Pamplona, Spain. , (Spain)
Type
Published Article
Journal
International Journal of Cancer
Publisher
Wiley (John Wiley & Sons)
Publication Date
Oct 01, 2019
Volume
145
Issue
7
Pages
1991–2001
Identifiers
DOI: 10.1002/ijc.32256
PMID: 30848481
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. © 2019 UICC.

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