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Ref Type Journal Article
PMID (35852858)
Authors Rehman H, Chandrashekar DS, Balabhadrapatruni C, Nepal S, Balasubramanya SAH, Shelton AK, Skinner KR, Ma AH, Rao T, Agarwal S, Eich ML, Robinson AD, Naik G, Manne U, Netto GJ, Miller CR, Pan CX, Sonpavde G, Varambally S, Ferguson JE
Title ARID1A-deficient bladder cancer is dependent on PI3K signaling and sensitive to EZH2 and PI3K inhibitors.
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Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ARID1A inact mut urinary bladder cancer sensitive MAK683 Preclinical - Cell culture Actionable In a preclinical study, MAK683 inhibited viability of bladder cancer cell lines harboring ARID1A inactivating mutations in culture (PMID: 35852858). 35852858
ARID1A inact mut urinary bladder cancer sensitive Pictilisib Preclinical - Cell culture Actionable In a preclinical study, Pictilisib (GDC-0941) inhibited viability of bladder cancer cell lines harboring ARID1A inactivating mutations in culture (PMID: 35852858). 35852858
ARID1A dec exp urinary bladder cancer sensitive Tazemetostat Preclinical - Cell culture Actionable In a preclinical study, Tazverik (tazemetostat) inhibited viability of bladder cancer cell lines with ARID1A knockdown in culture (PMID: 35852858). 35852858
ARID1A dec exp urinary bladder cancer sensitive GSK126 Preclinical - Cell culture Actionable In a preclinical study, GSK126 inhibited viability of bladder cancer cell lines with ARID1A knockdown in culture (PMID: 35852858). 35852858
ARID1A dec exp urinary bladder cancer sensitive CPI-1205 Preclinical - Cell culture Actionable In a preclinical study, CPI-1205 inhibited viability of bladder cancer cell lines with ARID1A knockdown in culture (PMID: 35852858). 35852858
ARID1A dec exp urinary bladder cancer sensitive Alpelisib Preclinical - Cell culture Actionable In a preclinical study, Piqray (alpelisib) inhibited viability of bladder cancer cell lines with ARID1A knockdown in culture (PMID: 35852858). 35852858
ARID1A dec exp urinary bladder cancer sensitive Dactolisib Preclinical - Cell culture Actionable In a preclinical study, Dactolisib (BEZ235) inhibited viability of bladder cancer cell lines with ARID1A knockdown in culture (PMID: 35852858). 35852858
ARID1A dec exp urinary bladder cancer sensitive GSK126 + Pictilisib Preclinical - Cell culture Actionable In a preclinical study, the combination of GSK126 and Pictilisib (GDC-0941) synergistically inhibited viability of bladder cancer cell lines with ARID1A knockdown in culture (PMID: 35852858). 35852858
ARID1A dec exp urinary bladder cancer sensitive Pictilisib Preclinical - Cell culture Actionable In a preclinical study, Pictilisib (GDC-0941) inhibited viability of bladder cancer cell lines with ARID1A knockdown in culture (PMID: 35852858). 35852858
ARID1A inact mut urinary bladder cancer sensitive CPI-1205 Preclinical - Cell culture Actionable In a preclinical study, CPI-1205 inhibited viability of bladder cancer cell lines harboring ARID1A inactivating mutations in culture (PMID: 35852858). 35852858
ARID1A inact mut urinary bladder cancer sensitive GSK126 Preclinical - Pdx & cell culture Actionable In a preclinical study, GSK126 inhibited cell viability in bladder cancer cell lines harboring ARID1A inactivating mutations in culture and inhibited tumor growth in patient-derived xenograft (PDX) and cell line xenograft models of bladder cancer harboring ARID1A inactivating mutations (PMID: 35852858). 35852858
ARID1A inact mut urinary bladder cancer sensitive Tazemetostat Preclinical - Cell culture Actionable In a preclinical study, Tazverik (tazemetostat) inhibited viability of bladder cancer cell lines harboring ARID1A inactivating mutations in culture (PMID: 35852858). 35852858
ARID1A dec exp urinary bladder cancer sensitive MAK683 Preclinical - Cell culture Actionable In a preclinical study, MAK683 inhibited viability of bladder cancer cell lines with ARID1A knockdown in culture (PMID: 35852858). 35852858