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Identification of mutations associated with acquired resistance to sunitinib in renal cell cancer.
Elgendy, Mohamed; Fusco, Juan Pablo; Segura, Victor; Lozano, Maria Dolores; Minucci, Saverio; Echeveste, Jose Ignacio; Gurpide, Alfonso; Andueza, Mapi; Melero, Ignacio; Sanmamed, Miguel F; Ruiz, Maria Rodriguez; Calvo, Alfonso; Pascual, Juan Ignacio; Velis, Jose María; Miñana, Bernardino; Valle, Ricardo Diez; Pio, Ruben; Agorreta, Jackeline; Abengozar, Marta; Colecchia, Maurizio; Brich, Silvia; Renne, Salvatore Lorenzo; Guruceaga, Elisabet; Patiño-García, Ana; Perez-Gracia, Jose Luis.
Afiliación
  • Elgendy M; Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
  • Fusco JP; Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria.
  • Segura V; Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain.
  • Lozano MD; Health Research Institute of Navarra (IDISNA), Pamplona, Spain.
  • Minucci S; Bioinformatics Unit, Center for Applied Medical Research (CIMA), IDISNA, University of Navarra, Pamplona, Spain.
  • Echeveste JI; Health Research Institute of Navarra (IDISNA), Pamplona, Spain.
  • Gurpide A; Pathology Department, Clinica Universidad de Navarra, Pamplona, Spain.
  • Andueza M; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain.
  • Melero I; Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
  • Sanmamed MF; Department of Biosciences, University of Milan, Milan, Italy.
  • Ruiz MR; Health Research Institute of Navarra (IDISNA), Pamplona, Spain.
  • Calvo A; Pathology Department, Clinica Universidad de Navarra, Pamplona, Spain.
  • Pascual JI; Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain.
  • Velis JM; Health Research Institute of Navarra (IDISNA), Pamplona, Spain.
  • Miñana B; Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain.
  • Valle RD; Health Research Institute of Navarra (IDISNA), Pamplona, Spain.
  • Pio R; Health Research Institute of Navarra (IDISNA), Pamplona, Spain.
  • Agorreta J; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain.
  • Abengozar M; Department of Immunology, Center for Applied Medical Research (CIMA), Pamplona, Spain.
  • Colecchia M; Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain.
  • Brich S; Health Research Institute of Navarra (IDISNA), Pamplona, Spain.
  • Renne SL; Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain.
  • Guruceaga E; Health Research Institute of Navarra (IDISNA), Pamplona, Spain.
  • Patiño-García A; Health Research Institute of Navarra (IDISNA), Pamplona, Spain.
  • Perez-Gracia JL; Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain.
Int J Cancer ; 145(7): 1991-2001, 2019 10 01.
Article en En | MEDLINE | ID: mdl-30848481
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Células Renales / Biomarcadores de Tumor / Resistencia a Antineoplásicos / Neoplasias Renales / Mutación Tipo de estudio: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Límite: Animals / Female / Humans Idioma: En Revista: Int J Cancer Año: 2019 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Células Renales / Biomarcadores de Tumor / Resistencia a Antineoplásicos / Neoplasias Renales / Mutación Tipo de estudio: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Límite: Animals / Female / Humans Idioma: En Revista: Int J Cancer Año: 2019 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Estados Unidos