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Ref Type Journal Article
PMID (26069190)
Authors Shen J, Peng Y, Wei L, Zhang W, Yang L, Lan L, Kapoor P, Ju Z, Mo Q, Shih IeM, Uray IP, Wu X, Brown PH, Shen X, Mills GB, Peng G
Title ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors.
Journal Cancer discovery
Vol 5
Issue 7
Date 2015 Jul
URL
Abstract Text ARID1A, SWI/SNF chromatin remodeling complex subunit, is a recently identified tumor suppressor that is mutated in a broad spectrum of human cancers. Thus, it is of fundamental clinical importance to understand its molecular functions and determine whether ARID1A deficiency can be exploited therapeutically. In this article, we report a key function of ARID1A in regulating the DNA damage checkpoint. ARID1A is recruited to DNA double-strand breaks (DSB) via its interaction with the upstream DNA damage checkpoint kinase ATR. At the molecular level, ARID1A facilitates efficient processing of DSB to single-strand ends and sustains DNA damage signaling. Importantly, ARID1A deficiency sensitizes cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with ARID1A-mutant tumors.ARID1A has been identified as one of the most frequently mutated genes across human cancers. Our data suggest that clinical utility of PARP inhibitors might be extended beyond patients with BRCA mutations to a larger group of patients with ARID1A-mutant tumors, which may exhibit therapeutic vulnerability to PARP inhibitors.

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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 A339Gfs*61 frameshift loss of function - predicted ARID1A A339Gfs*61 indicates a shift in the reading frame starting at amino acid 339 and terminating 61 residues downstream causing a premature truncation of the 2285 amino acid Arid1a protein (UniProt.org). A339Gfs*61 has not been characterized, however, due to the effects of other truncation mutations downstream of A339 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A A339Lfs*24 frameshift loss of function - predicted ARID1A A339Lfs*24 indicates a shift in the reading frame starting at amino acid 339 and terminating 24 residues downstream causing a premature truncation of the 2285 amino acid Arid1a protein (UniProt.org). A339Lfs*24 has not been characterized, however, due to the effects of other truncation mutations downstream of A339 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A G276* nonsense loss of function - predicted ARID1A G276* results in a premature truncation of the Arid1a protein at amino acid 276 of 2285 (UniProt.org). G276* has not been characterized, however, due to the effects of other truncation mutations downstream of G276 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A G276Efs*87 frameshift loss of function - predicted ARID1A G276Efs*87 indicates a shift in the reading frame starting at amino acid 726 and terminating 87 residues downstream causing a premature truncation of the 2285 amino acid Arid1a protein (UniProt.org). G276Efs*87 has not been characterized, however, due to the effects of other truncation mutations downstream of G276 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A G283fs frameshift loss of function - predicted ARID1A G283fs results in a change in the amino acid sequence of the Arid1a protein beginning at aa 283 of 2285, likely resulting in premature truncation of the functional protein (UniProt.org). G283fs has not been characterized, however, due to the effects of other truncation mutations downstream of G283 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A G284fs frameshift loss of function - predicted ARID1A G284fs results in a change in the amino acid sequence of the Arid1a protein beginning at aa 284 of 2285, likely resulting in premature truncation of the functional protein (UniProt.org). G284fs has not been characterized, however, due to the effects of other truncation mutations downstream of G284 (PMID: 29736026, PMID: 26069190), is predicted to lead to a loss of Arid1a protein function.
ARID1A G319fs frameshift loss of function - predicted ARID1A G319fs results in a change in the amino acid sequence of the Arid1a protein beginning at aa 319 of 2285, likely resulting in premature truncation of the functional protein (UniProt.org). G319fs has not been characterized, however, due to the effects of other truncation mutations downstream of G319 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A H203fs frameshift loss of function - predicted ARID1A H203fs results in a change in the amino acid sequence of the Arid1a protein beginning at aa 203 of 2285, likely resulting in premature truncation of the functional protein (UniProt.org). H203fs has not been characterized, however, due to the effects of other truncation mutations downstream of H203 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A P135Lfs*96 frameshift loss of function - predicted ARID1A P135Lfs*96 indicates a shift in the reading frame starting at amino acid 135 and terminating 96 residues downstream causing a premature truncation of the 2285 amino acid Arid1a protein (UniProt.org). P135Lfs*96 has not been characterized, however, due to the effects of other truncation mutations downstream of P135 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A P224fs frameshift loss of function - predicted ARID1A P224fs results in a change in the amino acid sequence of the Arid1a protein beginning at aa 224 of 2285, likely resulting in premature truncation of the functional protein (UniProt.org). P224fs has not been characterized, however, due to the effects of other truncation mutations downstream of P224 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A P224Rfs*8 frameshift loss of function - predicted ARID1A P224Rfs*8 indicates a shift in the reading frame starting at amino acid 224 and terminating 8 residues downstream causing a premature truncation of the 2285 amino acid Arid1a protein (UniProt.org). P224Rfs*8 has not been characterized, however, due to the effects of other truncation mutations downstream of P224 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A P94Lfs*7 frameshift loss of function - predicted ARID1A P94Lfs*7 indicates a shift in the reading frame starting at amino acid 94 and terminating 7 residues downstream causing a premature truncation of the 2285 amino acid Arid1a protein (UniProt.org). P94Lfs*7 has not been characterized, however, due to the effects of other truncation mutations downstream of P94 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A Q199* nonsense loss of function - predicted ARID1A Q199* results in a premature truncation of the Arid1a protein at amino acid 199 of 2285 (UniProt.org). Q199* has not been characterized, however, due to the effects of other truncation mutations downstream of Q199 (PMID: 29736026, PMID: 26069190), is predicted to lead to a loss of Arid1a protein function.
ARID1A Q199fs frameshift loss of function - predicted ARID1A Q199fs results in a change in the amino acid sequence of the Arid1a protein beginning at aa 199 of 2285, likely resulting in premature truncation of the functional protein (UniProt.org). Q199fs has not been characterized, however, due to the effects of other truncation mutations downstream of Q199 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A Q288Pfs*112 frameshift loss of function - predicted ARID1A Q288Pfs*112 indicates a shift in the reading frame starting at amino acid 288 and terminating 112 residues downstream causing a premature truncation of the 2285 amino acid Arid1a protein (UniProt.org). Q288Pfs*112 has not been characterized, however, due to the effects of other truncation mutations downstream of Q288 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A Q372* nonsense loss of function - predicted ARID1A Q372* results in a premature truncation of the Arid1a protein at amino acid 372 of 2285 (UniProt.org). Q372* has not been characterized, however, due to the effects of other truncation mutations downstream of Q372 (PMID: 29736026, PMID: 26069190), is predicted to lead to a loss of Arid1a protein function.
ARID1A Q372Afs*28 frameshift loss of function - predicted ARID1A Q372Afs*28 indicates a shift in the reading frame starting at amino acid 372 and terminating 28 residues downstream causing a premature truncation of the 2285 amino acid Arid1a protein (UniProt.org). Q372Afs*28 has not been characterized, however, due to the effects of other truncation mutations downstream of Q372 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A Q372Sfs*19 frameshift loss of function - predicted ARID1A Q372Sfs*19 indicates a shift in the reading frame starting at amino acid 372 and terminating 19 residues downstream causing a premature truncation of the 2285 amino acid Arid1a protein (UniProt.org). Q372Sfs*19 has not been characterized, however, due to the effects of other truncation mutations downstream of Q372 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A Q393* nonsense loss of function - predicted ARID1A Q393* results in a premature truncation of the Arid1a protein at amino acid 393 of 2285 (UniProt.org). Q393* has not been characterized, however, due to the effects of other truncation mutations downstream of Q393 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A Q393fs frameshift loss of function - predicted ARID1A Q393fs results in a change in the amino acid sequence of the Arid1a protein beginning at aa 393 of 2285, likely resulting in premature truncation of the functional protein (UniProt.org). Q393fs has not been characterized, however, due to the effects of other truncation mutations downstream of Q393 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function
ARID1A Q403* nonsense loss of function - predicted ARID1A Q403* results in a premature truncation of the Arid1a protein at amino acid 403 of 2285 (UniProt.org). Q403* has not been characterized, however, due to the effects of other truncation mutations downstream of Q403 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A Q449* nonsense loss of function - predicted ARID1A Q449* results in a premature truncation of the Arid1a protein at amino acid 449 of 2285 (UniProt.org). Q449* has not been characterized, however, due to the effects of other truncation mutations downstream of Q449 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A Q456* nonsense loss of function ARID1A Q456* results in a premature truncation of the Arid1a protein at amino acid 456 of 2285 (UniProt.org). Q456* confers a loss of function to the Arid1a protein as demonstrated by loss of Arid1a protein expression, disruption of the G2-M cell cycle checkpoint, decreased gamma-H2AX and 53BP1 foci, and decreased efficiency of homologous recombination and single-strand annealing repair of DNA in cultured cells (PMID: 26069190).
ARID1A S11fs frameshift loss of function - predicted ARID1A S11fs results in a change in the amino acid sequence of the Arid1a protein beginning at aa 11 of 2285, likely resulting in premature truncation of the functional protein (UniProt.org). S11fs has not been characterized, however, due to the effects of other truncation mutations downstream of S11 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A S138* nonsense loss of function - predicted ARID1A S138* results in a premature truncation of the Arid1a protein at amino acid 138 of 2285 (UniProt.org). S138* has not been characterized, however, due to the effects of other truncation mutations downstream of S138 (PMID: 29736026, PMID: 26069190), is predicted to lead to a loss of Arid1a protein function.
ARID1A S261* nonsense loss of function - predicted ARID1A S261* results in a premature truncation of the Arid1a protein at amino acid 261 of 2285 (UniProt.org). S261* has not been characterized, however, due to the effects of other truncation mutations downstream of S261 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A S264* nonsense loss of function - predicted ARID1A S264* results in a premature truncation of the Arid1a protein at amino acid 264 of 2285 (UniProt.org). S264* has not been characterized, however, due to the effects of other truncation mutations downstream of S264 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A T294Pfs*69 frameshift loss of function - predicted ARID1A T294Pfs*69 indicates a shift in the reading frame starting at amino acid 294 and terminating 69 residues downstream causing a premature truncation of the 2285 amino acid Arid1a protein (UniProt.org). T294Pfs*69 has not been characterized, however, due to the effects of other truncation mutations downstream of T294 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ARID1A dec exp breast cancer sensitive Rucaparib Preclinical - Cell culture Actionable In a preclinical study, Rubraca (rucaparib) inhibited colony formation of human mammary epithelial cells and inhibited proliferation of a human breast cancer cell line after knockdown of ARID1A in culture (PMID: 26069190). 26069190
ARID1A Q456* colorectal cancer sensitive Olaparib Preclinical Actionable In a preclinical study, Lynparza (olaparib) inhibited proliferation and colony formation of a colorectal cancer cell line harboring ARID1A Q456* in culture (PMID: 26069190). 26069190
ARID1A Q456* colorectal cancer sensitive Talazoparib Preclinical - Cell line xenograft Actionable In a preclinical study, Talazoparib (BMN-673) inhibited colony formation and proliferation of a human colorectal cancer cell line harboring ARID1A Q456* in culture and inhibited tumor formation in colorectal cancer xenografts harboring ARID1A Q456* (PMID: 26069190). 26069190
ARID1A Q456* colorectal cancer sensitive Rucaparib Preclinical - Cell culture Actionable In a preclinical study, Rubraca (rucaparib) treatment resulted in increased apoptosis of colorectal cancer cells harboring ARID1A Q456* in culture (PMID: 26069190). 26069190
ARID1A dec exp breast cancer conflicting Talazoparib Preclinical - Cell line xenograft Actionable In a preclinical study, Talazoparib (BMN-673) selectively inhibited growth and induced apoptosis in breast cancer cells with knock-down of ARID1A in culture, and inhibited tumor growth in ARID1A-deficient breast cancer cell line xenograft models (PMID: 26069190). 26069190
ARID1A dec exp breast cancer sensitive Olaparib Preclinical Actionable In a preclinical study, Lynparza (olaparib) inhibited colony formation of human mammary epithelial cells and inhibited proliferation of a human breast cancer cell line after knockdown of ARID1A in culture (PMID: 26069190). 26069190
ARID1A dec exp breast cancer sensitive Veliparib Preclinical - Cell culture Actionable In a preclinical study, Veliparib (ABT-888) inhibited colony formation of human mammary epithelial cells and inhibited proliferation of a human breast cancer cell line after knockdown of ARID1A in culture (PMID: 26069190). 26069190
ARID1A dec exp ovarian cancer sensitive Talazoparib Preclinical - Cell culture Actionable In a preclinical study, knockdown of ARID1A resulted in increased sensitivity to Talazoparib (BMN-673) in ovarian cancer cells in culture (PMID: 26069190). 26069190