TY - JOUR
T1 - EZH2 modifies sunitinib resistance in renal cell carcinoma by kinome reprogramming
AU - Adelaiye-Ogala, Remi
AU - Budka, Justin
AU - Damayanti, Nur P.
AU - Arrington, Justine
AU - Ferris, Mary
AU - Hsu, Chuan Chih
AU - Chintala, Sreenivasulu
AU - Orillion, Ashley
AU - Miles, Kiersten Marie
AU - Shen, Li
AU - Elbanna, May
AU - Ciamporcero, Eric
AU - Arisa, Sreevani
AU - Pettazzoni, Piergiorgio
AU - Draetta, Giulio F.
AU - Seshadri, Mukund
AU - Hancock, Bradley
AU - Radovich, Milan
AU - Kota, Janaiah
AU - Buck, Michael
AU - Keilhack, Heike
AU - McCarthy, Brian P.
AU - Persohn, Scott A.
AU - Territo, Paul R.
AU - Zang, Yong
AU - Irudayaraj, Joseph
AU - Tao, W. Andy
AU - Hollenhorst, Peter
AU - Pili, Roberto
N1 - Publisher Copyright:
©2017 AACR.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-17-0899
DO - 10.1158/0008-5472.CAN-17-0899
M3 - Article
C2 - 28978636
AN - SCOPUS:85037704869
SN - 0008-5472
VL - 77
SP - 6651
EP - 6666
JO - Cancer Research
JF - Cancer Research
IS - 23
ER -