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
  • 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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