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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Metastatic urothelial carcinoma remains largely incurable with existing treatments.
• ARID1A mutations are found in approximately 20% of bladder cancers and oppose the oncogenic function of EZH2.
• PI3K signaling is aberrantly activated in over 20% of bladder cancers.

Purpose of the Study:

• To investigate the therapeutic potential of EZH2 and PI3K inhibitors in ARID1A-mutant bladder cancer.
• To elucidate the underlying molecular mechanisms connecting ARID1A deficiency, EZH2 inhibition sensitivity, and PI3K signaling.
• To evaluate the efficacy of combination therapy targeting EZH2 and PI3K in ARID1A-deficient bladder cancer models.

Main Methods:

• In vitro and in vivo experiments utilizing patient-derived xenografts.
• Analysis of signaling pathway dependencies in ARID1A-mutant versus wild-type bladder cancer cells.
• Assessment of sensitivity to EZH2 inhibitors and combination therapy with PI3K inhibitors.

Main Results:

• ARID1A-mutant tumors exhibited greater sensitivity to EZH2 inhibition compared to ARID1A wild-type tumors.
• ARID1A deficiency leads to increased reliance on PI3K/AKT/mTOR signaling through PIK3R3 upregulation and MAPK signaling downregulation.
• EZH2 inhibitor sensitivity was linked to PIK3IP1 upregulation, which inhibits PI3K signaling by promoting PIK3R3 proteasomal degradation.
• Combination therapy with EZH2 and PI3K inhibitors demonstrated synergistic effects in ARID1A-deficient bladder cancer.

Conclusions:

• Bladder cancers with ARID1A mutations represent a targetable subset for EZH2 and/or PI3K inhibitor therapies.
• Noncanonical PI3K pathway constituents play a critical role in bladder cancer biology and therapeutic response.
• Targeting EZH2 and PI3K pathways offers a synergistic therapeutic strategy for ARID1A-mutant urothelial carcinoma.