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Cancer Res. 2017 Dec 1;77(23):6651-6666. doi: 10.1158/0008-5472.CAN-17-0899. Epub 2017 Oct 4.

EZH2 Modifies Sunitinib Resistance in Renal Cell Carcinoma by Kinome Reprogramming.

Author information

1
Department of Cancer Pathology and Prevention, University at Buffalo, Buffalo, New York.
2
Department of Pharmacology and Toxicology, Indiana University, Indianapolis, Indiana.
3
Medical Sciences, Indiana University, Bloomington, Indiana.
4
Department of Biomedical Engineering, Purdue University, West Lafayette, Indiana.
5
Department of Biochemistry, Purdue University, West Lafayette, Indiana.
6
Department of Medicine, Indiana University, Indianapolis, Indiana.
7
Department of Cellular and Molecular Biology, University at Buffalo, Buffalo, New York.
8
Center for Personalized Medicine, Roswell Park Cancer Institute, New York, New York.
9
Department of Medicine, Roswell Park Cancer Institute, New York, New York.
10
Department of Medicine and Experimental Oncology, University of Turin, Turin, Italy.
11
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
12
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
13
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, New York, New York.
14
Department of Surgery, Indiana University, Indianapolis, Indiana.
15
Department of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana.
16
Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, Buffalo, New York.
17
Epizyme Inc., Cambridge, Massachusetts.
18
Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, Indiana.
19
Department of Biostatistics, Indiana University, Indianapolis, Indiana.
20
Medical Sciences, Indiana University, Bloomington, Indiana. pchollen@indiana.edu rpili@iu.edu.
21
Department of Cancer Pathology and Prevention, University at Buffalo, Buffalo, New York. pchollen@indiana.edu rpili@iu.edu.

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. Cancer Res; 77(23); 6651-66. ©2017 AACR.

PMID:
28978636
PMCID:
PMC5712262
DOI:
10.1158/0008-5472.CAN-17-0899
[Indexed for MEDLINE]
Free PMC Article

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