TY - JOUR
T1 - ARID1A-deficient bladder cancer is dependent on PI3K signaling and sensitive to EZH2 and PI3K inhibitors
AU - Rehman, Hasibur
AU - Chandrashekar, Darshan S.
AU - Balabhadrapatruni, Chakravarthi
AU - Nepal, Saroj
AU - Balasubramanya, Sai Akshaya Hodigere
AU - Shelton, Abigail K.
AU - Skinner, Kasey R.
AU - Ma, Ai Hong
AU - Rao, Ting
AU - Agarwal, Sumit
AU - Eich, Marie Lisa
AU - Robinson, Alyncia D.
AU - Naik, Gurudatta
AU - Manne, Upender
AU - Netto, George J.
AU - Ryan Miller, C.
AU - Pan, Chong Xian
AU - Sonpavde, Guru
AU - Varambally, Sooryanarayana
AU - Ferguson, James E.
N1 - Publisher Copyright:
© 2022 American Society for Clinical Investigation. All rights reserved.
PY - 2022/8/22
Y1 - 2022/8/22
N2 - 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 were more sensitive to EZH2 inhibition than ARID1A WT tumors. Mechanistic studies revealed that (a) ARID1A deficiency results in a dependency on PI3K/ AKT/mTOR signaling via upregulation of a noncanonical PI3K regulatory subunit, PIK3R3, and downregulation of MAPK signaling and (b) EZH2 inhibitor sensitivity is due to upregulation of PIK3IP1, a protein inhibitor of PI3K signaling. We show that PIK3IP1 inhibited PI3K signaling by inducing proteasomal degradation of PIK3R3. Furthermore, ARID1A-deficient bladder cancer was 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 revealed mechanistic insights into the role of noncanonical PI3K constituents in bladder cancer biology.
AB - 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 were more sensitive to EZH2 inhibition than ARID1A WT tumors. Mechanistic studies revealed that (a) ARID1A deficiency results in a dependency on PI3K/ AKT/mTOR signaling via upregulation of a noncanonical PI3K regulatory subunit, PIK3R3, and downregulation of MAPK signaling and (b) EZH2 inhibitor sensitivity is due to upregulation of PIK3IP1, a protein inhibitor of PI3K signaling. We show that PIK3IP1 inhibited PI3K signaling by inducing proteasomal degradation of PIK3R3. Furthermore, ARID1A-deficient bladder cancer was 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 revealed mechanistic insights into the role of noncanonical PI3K constituents in bladder cancer biology.
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U2 - 10.1172/jci.insight.155899
DO - 10.1172/jci.insight.155899
M3 - Article
C2 - 35852858
AN - SCOPUS:85136293848
SN - 2379-3708
VL - 7
JO - JCI Insight
JF - JCI Insight
IS - 16
M1 - e155899
ER -