Transcriptomic profiling for differential gene expression in ARID1A-wt and ARID1A-deficient bladder cancer cells with and without GSK126 (an EZH2 inhibitor) treatment

Metastatic urothelial carcinoma of the bladder is generally incurable with current systemic therapies. Chromatin modifiers are frequently mutated in bladder cancer, with ARID1A inactivating mutations present in 20% of tumors. EZH2 is a histone methyltransferase that acts as an oncogene that functionally opposes ARID1A. In addition, PI3K signaling is activated in over 20% of bladder cancers. Here 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 upregulation of a non-canonical PI3K regulatory subunit PIK3R3, and: 2) EZH2 inhibitor sensitivity is due to upregulation of PIK3IP1, an inhibitor protein of PI3K signaling. Thus, our studies suggest that a subset of bladder cancers with ARID1A mutations can be treated with inhibitors of EZH2 and/or PI3K, and reveal novel mechanistic insights into the role of non-canonical PI3K constituents in bladder cancer biology. Overall design: mRNA sequencing of ARID1A-wt and ARID1A-deficient bladder cancer cells (RT112) treated with either DMSO control or GSK126