Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
JCI insight	7	16	2022 Aug 22		JCI Insight

URL

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 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	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	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 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	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	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 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	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
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	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	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	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