Citation Information: JCI Insight. 2022. https://doi.org/10.1172/jci.insight.155899.
Abstract
Metastatic urothelial carcinoma is generally incurable with current systemic therapies. Chromatin modifiers are frequently mutated in bladder cancer, with ARID1A-inactivating mutations present in about 20% of tumors. EZH2, a histone methyltransferase, acts as an oncogene that functionally opposes ARID1A. In addition, PI3K signaling is activated in more than 20% of bladder cancers. Using a combination of in vitro and in vivo data, including patient derived xenografts, we show that ARID1A-mutant tumors are more sensitive to EZH2 inhibition than ARID1A-wild type tumors. Mechanistic studies reveal that: 1) ARID1A deficiency results in a dependency on PI3K/AKT/mTOR signaling via novel upregulation of a non-canonical PI3K regulatory subunit, PIK3R3, and downregulation of MAPK signaling, and: 2) EZH2 inhibitor sensitivity is due to upregulation of PIK3IP1, a protein inhibitor of PI3K signaling. We show for the first time that PIK3IP1 inhibits PI3K signaling by inducing proteasomal degradation of PIK3R3. Further, ARID1A deficient bladder cancer is sensitive to combination therapies with EZH2 and PI3K inhibitors, in a synergistic manner. Thus, our studies suggest that bladder cancers with ARID1A mutations can be treated with inhibitors of EZH2 and/or PI3K, and reveal mechanistic insights into the role of non-canonical PI3K constituents in bladder cancer biology.
Authors
Hasibur Rehman, Darshan S. Chandrashekar, Chakravarthi Balabhadrapatruni, Saroj Nepal, Sai Akshaya Hodigere Balasubramanya, Abigail K. Shelton, Kasey R. Skinner, Ai-Hong Ma, Ting Rao, Marie-Lisa Eich, Alyncia D. Robinson, Gurudatta Naik, Upender Manne, George J. Netto, C. Ryan Miller, Chong-xian Pan, Guru Sonpavde, Sooryanarayana Varambally, James E. Ferguson 3rd
