EZH2 modifies sunitinib resistance in renal cell carcinoma by kinome reprogramming

Remi Adelaiye-Ogala, Justin Budka, Nur P. Damayanti, Justine Arrington, Mary Ferris, Chuan Chih Hsu, Sreenivasulu Chintala, Ashley Orillion, Kiersten Marie Miles, Li Shen, May Elbanna, Eric Ciamporcero, Sreevani Arisa, Piergiorgio Pettazzoni, Giulio F. Draetta, Mukund Seshadri, Bradley Hancock, Milan Radovich, Janaiah Kota, Michael BuckHeike Keilhack, Brian P. McCarthy, Scott A. Persohn, Paul R. Territo, Yong Zang, Joseph Irudayaraj, W. Andy Tao, Peter Hollenhorst, Roberto Pili

Research output: Contribution to journalArticle

Abstract

Acquired and intrinsic resistance to receptor tyrosine kinase inhibitors (RTKi) represents a major hurdle in improving the management of clear cell renal cell carcinoma (ccRCC). Recent reports suggest that drug resistance is driven by tumor adaptation via epigenetic mechanisms that activate alternative survival pathways. The histone methyl transferase EZH2 is frequently altered in many cancers, including ccRCC. To evaluate its role in ccRCC resistance to RTKi, we established and characterized a spontaneously metastatic, patient-derived xenograft model that is intrinsically resistant to the RTKi sunitinib, but not to the VEGF therapeutic antibody bevacizumab. Sunitinib maintained its antiangiogenic and antimetastatic activity but lost its direct antitumor effects due to kinome reprogramming, which resulted in suppression of proapoptotic and cell-cycle–regulatory target genes. Modulating EZH2 expression or activity suppressed phosphorylation of certain RTKs, restoring the antitumor effects of sunitinib in models of acquired or intrinsically resistant ccRCC. Overall, our results highlight EZH2 as a rational target for therapeutic intervention in sunitinib-resistant ccRCC as well as a predictive marker for RTKi response in this disease.

Original languageEnglish (US)
Pages (from-to)6651-6666
Number of pages16
JournalCancer Research
Volume77
Issue number23
DOIs
StatePublished - Dec 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Adelaiye-Ogala, R., Budka, J., Damayanti, N. P., Arrington, J., Ferris, M., Hsu, C. C., Chintala, S., Orillion, A., Miles, K. M., Shen, L., Elbanna, M., Ciamporcero, E., Arisa, S., Pettazzoni, P., Draetta, G. F., Seshadri, M., Hancock, B., Radovich, M., Kota, J., ... Pili, R. (2017). EZH2 modifies sunitinib resistance in renal cell carcinoma by kinome reprogramming. Cancer Research, 77(23), 6651-6666. https://doi.org/10.1158/0008-5472.CAN-17-0899