Identification of mutations associated with acquired resistance to sunitinib in renal cell cancer: International Journal of Cancer

M. Elgendy, J.P. Fusco, V. Segura, M.D. Lozano, S. Minucci, J.I. Echeveste, A. Gurpide, M. Andueza, I. Melero, M.F. Sanmamed, M.R. Ruiz, A. Calvo, J.I. Pascual, J.M. Velis, B. Miñana, R.D. Valle, R. Pio, J. Agorreta, M. Abengozar, M. ColecchiaS. Brich, S.L. Renne, E. Guruceaga, A. Patiño-García, J.L. Perez-Gracia

Research output: Contribution to journalArticle

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
Original languageEnglish
Pages (from-to)1991-2001
Number of pages11
JournalInt. J. Cancer
Volume145
Issue number7
DOIs
Publication statusPublished - 2019

Keywords

  • biomarkers
  • DCC
  • G6PD
  • LRP1B
  • MCL-1
  • mTORC1
  • renal cell carcinoma
  • resistance
  • SETD2
  • sunitinib
  • SYNE1
  • TET2
  • cabozantinib
  • everolimus
  • glucose 6 phosphate dehydrogenase
  • lenvatinib
  • netrin receptor DCC
  • tumor marker
  • animal experiment
  • animal model
  • Article
  • cancer patient
  • cancer resistance
  • cancer tissue
  • cell lysate
  • cohort analysis
  • computer model
  • controlled study
  • DCC gene
  • drug cytotoxicity
  • drug exposure
  • drug sensitivity
  • female
  • G6PD gene
  • gene
  • gene mutation
  • genetic association
  • human
  • human cell
  • human tissue
  • immunoblotting
  • in vitro study
  • in vivo study
  • loss of function mutation
  • low drug dose
  • LRP1B gene
  • major clinical study
  • mouse
  • mutational analysis
  • next generation sequencing
  • nonhuman
  • oncogene
  • priority journal
  • protein expression
  • protein function
  • sequence analysis
  • SETD2 gene
  • SYNE1 gene
  • TET2 gene
  • tumor suppressor gene
  • tumor xenograft
  • animal
  • cancer transplantation
  • DNA sequence
  • drug resistance
  • exon
  • gene expression regulation
  • genetics
  • kidney tumor
  • metabolism
  • mutation
  • tumor cell line
  • Animals
  • Biomarkers, Tumor
  • Carcinoma, Renal Cell
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Exons
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kidney Neoplasms
  • Mice
  • Mutation
  • Neoplasm Transplantation
  • Sequence Analysis, DNA
  • Sunitinib

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  • Cite this

    Elgendy, M., Fusco, J. P., Segura, V., Lozano, M. D., Minucci, S., Echeveste, J. I., Gurpide, A., Andueza, M., Melero, I., Sanmamed, M. F., Ruiz, M. R., Calvo, A., Pascual, J. I., Velis, J. M., Miñana, B., Valle, R. D., Pio, R., Agorreta, J., Abengozar, M., ... Perez-Gracia, J. L. (2019). Identification of mutations associated with acquired resistance to sunitinib in renal cell cancer: International Journal of Cancer. Int. J. Cancer, 145(7), 1991-2001. https://doi.org/10.1002/ijc.32256