ARID1A-mutant and deficient bladder cancer is sensitive to EZH2 pharmacologic inhibition
Ferguson, J. E.; Rehman, H.; Chandrashekar, D. S.; Chakravarthi, B.; Nepal, S.; Eich, M.-L.; Robinson, A.; Agarwal, S.; Balasubramanya, S. A. H.; Naik, G.; Manne, U.; Netto, G.; Pan, C.-x.; Sonpavde, G.; Varambally, S.
Show abstract
Metastatic urothelial carcinoma of the bladder is generally incurable by current systemic therapy. Molecular characterization of bladder cancer (BLCa) has revealed multiple candidate driver genes for BLCa tumorigenesis. Epigenetic/chromatin modifiers have been shown to be frequently mutated in BLCa, with ARID1A mutations highly prevalent in nearly 20% of early and late stage tumors. EZH2 is a histone methyltransferase that acts as an oncogene. The data herein show that ARID1A deficient tumors, but not ARID1A wild-type tumors are sensitive to EZH2 inhibition. Specifically, EZH2 inhibitor-treated ARID1A deficient bladder cancer cells show significantly reduced cell viability, colony formation, and in vivo tumor growth relative to ARID1A-wild type bladder cancer cells. Thus, our study suggests that a specific subset of bladder cancer patients with ARID1A mutations can be therapeutically treated with pharmacologic inhibitors targeting EZH2.
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