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PMID: 28978636 Published · ppublish English Journal Article

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

Cancer research ·Vol. 77 ·No. 23 ·2017-00-01 ·Pages 6651-6666

Adelaiye-Ogala R, Budka J, Damayanti NP, Arrington J, Ferris M, Hsu CC, Chintala S, Orillion A, Miles KM, Shen L, Elbanna M, Ciamporcero E, Arisa S, Pettazzoni P, Draetta GF, Seshadri M, Hancock B, Radovich M, Kota J, Buck M, Keilhack H, McCarthy BP, Persohn SA, Territo PR, Zang Y, Irudayaraj J, Tao WA, Hollenhorst P, Pili R

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.

MeSH Terms
Animals Antineoplastic Agents/pharmacology Bevacizumab/pharmacology Carcinoma, Renal Cell/drug therapy,pathology Cell Line, Tumor Drug Resistance, Neoplasm/physiology Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors,genetics,metabolism Female Humans Indoles/pharmacology Kidney Neoplasms/drug therapy,pathology Lung Neoplasms/drug therapy,secondary Mice Mice, Inbred ICR Mice, SCID Neovascularization, Pathologic/drug therapy Phosphorylation Pyrroles/pharmacology Receptor Protein-Tyrosine Kinases/antagonists & inhibitors,metabolism Sunitinib Vascular Endothelial Growth Factor A/antagonists & inhibitors Xenograft Model Antitumor Assays
Chemicals
Antineoplastic Agents Indoles Pyrroles VEGFA protein, human Vascular Endothelial Growth Factor A Bevacizumab EZH2 protein, human Enhancer of Zeste Homolog 2 Protein Receptor Protein-Tyrosine Kinases Sunitinib
Authors & Affiliations
29 authors, click to expand affiliations / ORCID
Adelaiye-Ogala Remi
Department of Cancer Pathology and Prevention, University at Buffalo, Buffalo, New York. | Department of Pharmacology and Toxicology, Indiana University, Indianapolis, Indiana.
Budka Justin
Medical Sciences, Indiana University, Bloomington, Indiana.
Damayanti Nur P
Department of Biomedical Engineering, Purdue University, West Lafayette, Indiana.
Arrington Justine
Department of Biochemistry, Purdue University, West Lafayette, Indiana.
Ferris Mary
Medical Sciences, Indiana University, Bloomington, Indiana.
Hsu Chuan-Chih
Department of Biochemistry, Purdue University, West Lafayette, Indiana.
Chintala Sreenivasulu
Department of Medicine, Indiana University, Indianapolis, Indiana.
Orillion Ashley
Department of Pharmacology and Toxicology, Indiana University, Indianapolis, Indiana. | Department of Cellular and Molecular Biology, University at Buffalo, Buffalo, New York.
Miles Kiersten Marie
Center for Personalized Medicine, Roswell Park Cancer Institute, New York, New York.
Shen Li
Department of Medicine, Roswell Park Cancer Institute, New York, New York.
Elbanna May
Department of Pharmacology and Toxicology, Indiana University, Indianapolis, Indiana.
Ciamporcero Eric
Department of Medicine and Experimental Oncology, University of Turin, Turin, Italy.
Arisa Sreevani
Department of Medicine, Indiana University, Indianapolis, Indiana.
Pettazzoni Piergiorgio
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. | Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Draetta Giulio F
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. | Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Seshadri Mukund
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, New York, New York.
Hancock Bradley
Department of Surgery, Indiana University, Indianapolis, Indiana.
Radovich Milan
Department of Surgery, Indiana University, Indianapolis, Indiana.
Kota Janaiah
Department of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana.
Buck Michael
Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, Buffalo, New York.
Keilhack Heike
Epizyme Inc., Cambridge, Massachusetts.
McCarthy Brian P
Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, Indiana.
Persohn Scott A
Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, Indiana.
Territo Paul R
Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, Indiana.
Zang Yong
Department of Biostatistics, Indiana University, Indianapolis, Indiana.
Irudayaraj Joseph
Medical Sciences, Indiana University, Bloomington, Indiana.
Tao W Andy
Department of Biochemistry, Purdue University, West Lafayette, Indiana.
Hollenhorst Peter
Medical Sciences, Indiana University, Bloomington, Indiana. pchollen@indiana.edu rpili@iu.edu.
Pili Roberto
Department of Cancer Pathology and Prevention, University at Buffalo, Buffalo, New York. pchollen@indiana.edu rpili@iu.edu. | Department of Pharmacology and Toxicology, Indiana University, Indianapolis, Indiana. | Department of Medicine, Indiana University, Indianapolis, Indiana.
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Article Info
Journal
Cancer research
Abbr.
Cancer Res
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-17-0899
Email
pchollen@indiana.edu
rpili@iu.edu
Published
2017-00-01
Epub
2017-00-04
Pages
6651-6666
Language
English
Region
United States
NLM ID
2984705R
PMCID
PMC5712262
Subset
IM
Grants
NCRR NIH HHS · C06 RR020128 · United States
NCI NIH HHS · P30 CA016056 · United States
NCI NIH HHS · R01 CA135321 · United States
External Links
PubMed source DOI: 10.1158/0008-5472.CAN-17-0899 PMC Full Text View journal details
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