Reference Detail

Ref Type

Journal Article

PMID

(37306706)

Authors

Yu ZC, Li T, Tully E, Huang P, Chen CN, Oberdoerffer P, Gaillard S, Shih IM, Wang TL

Title

Temozolomide Sensitizes ARID1A-Mutated Cancers to PARP Inhibitors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	83	16	2023 Aug 15	2750-2762	Cancer Res

URL

Abstract Text

ARID1A is a subunit of SWI/SNF chromatin remodeling complexes and is mutated in many types of human cancers, especially those derived from endometrial epithelium, including ovarian and uterine clear cell carcinoma (CCC) and endometrioid carcinoma (EMCA). Loss-of-function mutations in ARID1A alter epigenetic regulation of transcription, cell-cycle checkpoint control, and DNA damage repair. We report here that mammalian cells with ARID1A deficiency harbor accumulated DNA base lesions and increased abasic (AP) sites, products of glycosylase in the first step of base excision repair (BER). ARID1A mutations also delayed recruitment kinetics of BER long-patch repair effectors. Although ARID1A-deficient tumors were not sensitive to monotherapy with DNA-methylating temozolomide (TMZ), the combination of TMZ with PARP inhibitors (PARPi) potently elicited double-strand DNA breaks, replication stress, and replication fork instability in ARID1A-deficient cells. The TMZ and PARPi combination also significantly delayed in vivo growth of ovarian tumor xenografts carrying ARID1A mutations and induced apoptosis and replication stress in xenograft tumors. Together, these findings identified a synthetic lethal strategy to enhance the response of ARID1A-mutated cancers to PARP inhibition, which warrants further experimental exploration and clinical trial validation.The combination of temozolomide and PARP inhibitor exploits the specific DNA damage repair status of ARID1A-inactivated ovarian cancers to suppress tumor growth.

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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
ARID1A	Q2209Sfs*22	frameshift	unknown	ARID1A Q2209Sfs22 indicates a shift in the reading frame starting at amino acid 2209 and terminating 22 residues downstream causing a premature truncation of the 2285 amino acid Arid1a protein (UniProt.org). Q2209Sfs22 has been identified in the scientific literature (PMID: 37306706), but has not been biochemically characterized and therefore, its effect on Arid1a protein function is unknown (PubMed, Mar 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ARID1A Q2209Sfs*22	ovarian cancer	sensitive	Olaparib + Temozolomide	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Lynparza (olaparib) and Temodar (temozolomide) inhibited viability of an ovarian cancer cell line harboring ARID1A Q2209Sfs*22 in culture (PMID: 37306706).	37306706
ARID1A Y551Lfs72 ARID1A Q758Rfs75	ovarian cancer	sensitive	Olaparib + Temozolomide	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of Lynparza (olaparib) and Temodar (temozolomide) synergistically inhibited viability of an ovarian cancer cell line harboring ARID1A Y551Lfs72 and Q758Rfs75 in culture and inhibited tumor growth in a cell line xenograft model (PMID: 37306706).	37306706
ARID1A Q586*	ovarian cancer	sensitive	Olaparib + Temozolomide	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Lynparza (olaparib) and Temodar (temozolomide) inhibited viability of an ovarian cancer cell line harboring ARID1A Q586* in culture (PMID: 37306706).	37306706
ARID1A Q1835* ARID1A Q2115*	ovarian cancer	sensitive	Olaparib + Temozolomide	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of Lynparza (olaparib) and Temodar (temozolomide) synergistically inhibited viability of an ovarian cancer cell line harboring ARID1A Q1835* and Q2115* in culture and inhibited tumor growth in a cell line xenograft model (PMID: 37306706).	37306706