2. Academic Validation
  3. ARID1A-deficient bladder cancer is dependent on PI3K signaling and sensitive to EZH2 and PI3K inhibitors

ARID1A-deficient bladder cancer is dependent on PI3K signaling and sensitive to EZH2 and PI3K inhibitors

  • JCI Insight. 2022 Aug 22;7(16):e155899. doi: 10.1172/jci.insight.155899.
Hasibur Rehman 1 2,  Darshan S Chandrashekar 2 3 4,  Chakravarthi Balabhadrapatruni 3,  Saroj Nepal 3,  Sai Akshaya Hodigere Balasubramanya 3,  Abigail K Shelton 3,  Kasey R Skinner 3 5,  Ai-Hong Ma 6,  Ting Rao 7,  Sumit Agarwal 3,  Marie-Lisa Eich 8,  Alyncia D Robinson 3,  Gurudatta Naik 2,  Upender Manne 2 3,  George J Netto 3,  C Ryan Miller 2 3,  Chong-Xian Pan 9,  Guru Sonpavde 10,  Sooryanarayana Varambally 2 3 4,  James E Ferguson 3rd 1 2 11
Affiliations

Affiliations

  • 1 Department of Urology.
  • 2 O'Neal Comprehensive Cancer Center.
  • 3 Department of Pathology, and.
  • 4 Informatics Institute, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • 5 Neuroscience Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
  • 6 Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, California, USA.
  • 7 Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China.
  • 8 Institute of Pathology, University Hospital Cologne, Cologne, Germany.
  • 9 Department of Medicine, Lank Center for Genitourinary Oncology, and.
  • 10 Department of Medicine, Dana-Farber Cancer Institute, Harvard Medical School Boston, Massachusetts, USA.
  • 11 Birmingham Veterans Affairs Medical Center, Birmingham, Alabama, USA.
PMID: 35852858 DOI: 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 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.

Keywords

Oncology; Urology.

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