Reference Detail

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
Variant Impact Protein Effect Variant Description Associated with drug Resistance
E1596* nonsense loss of function - predicted ARID1A E1596* results in a premature truncation of the Arid1a protein at amino acid 1596 of 2285 (UniProt.org). E1596* has not been characterized, however, due to the effects of truncation mutations downstream of E1596 (PMID: 26069190, PMID: 29736026), E1596* is predicted to lead to a loss of Arid1a protein function.
G1450fs frameshift loss of function - predicted ARID1A G1450fs results in a change in the amino acid sequence of the Arid1a protein beginning at aa 1450 of 2285, likely resulting in premature truncation of the functional protein (UniProt.org). G1450fs has not been characterized, however, due to the effects of truncation mutations downstream of G1450 (PMID: 26069190, PMID: 29736026), G1450fs is predicted to lead to a loss of Arid1a protein function.
K1071fs frameshift loss of function - predicted ARID1A K1071fs results in a change in the amino acid sequence of the Arid1a protein beginning at aa 1071 of 2285, likely resulting in premature truncation of the functional protein (UniProt.org). K1071fs has not been characterized, however, due to the effects of truncation mutations downstream of K1071 (PMID: 26069190, PMID: 29736026), K1071fs is predicted to lead to a loss of Arid1a protein function.
L1092* nonsense loss of function - predicted ARID1A L1092* results in a premature truncation of the Arid1a protein at amino acid 1092 of 2285 (UniProt.org). L1092* has not been characterized, however, due to the effects of truncation mutations downstream of L1092 (PMID: 26069190, PMID: 29736026), L1092* is predicted to lead to a loss of Arid1a protein function.
M1318fs frameshift loss of function - predicted ARID1A M1318fs results in a change in the amino acid sequence of the Arid1a protein beginning at aa 1318 of 2285, likely resulting in premature truncation of the functional protein (UniProt.org). M1318fs has not been characterized, however, due to the effects of truncation mutations downstream of M1318 (PMID: 26069190, PMID: 29736026), M1318fs is predicted to lead to a loss of Arid1a protein function.
Q1095* nonsense loss of function - predicted ARID1A Q1095* results in a premature truncation of the Arid1a protein at amino acid 1095 of 2285 (UniProt.org). Q1095* has not been characterized, however, due to the effects of truncation mutations downstream of Q1095 (PMID: 26069190, PMID: 29736026), Q1095* is predicted to lead to a loss of Arid1a protein function.
Q1131* nonsense loss of function - predicted ARID1A Q1131* results in a premature truncation of the Arid1a protein at amino acid 1131 of 2285 (UniProt.org). Q1131* has not been characterized, however, due to the effects of truncation mutations downstream of Q1131 (PMID: 26069190, PMID: 29736026), Q1131* is predicted to lead to a loss of Arid1a protein function.
Q1148* nonsense loss of function - predicted ARID1A Q1148* results in a premature truncation of the Arid1a protein at amino acid 1148 of 2285 (UniProt.org). Q1148* has not been characterized, however, due to the effects of truncation mutations downstream of Q1148 (PMID: 26069190, PMID: 29736026), Q1148* is predicted to lead to a loss of Arid1a protein function.
Q1172* nonsense loss of function - predicted ARID1A Q1172* results in a premature truncation of the Arid1a protein at amino acid 1172 of 2285 (UniProt.org). Q1172* has not been characterized, however, because other truncation mutations downstream of Q1172 are inactivating, Q1172* is predicted to lead to a loss of Arid1a protein function (PMID: 26069190).
Q1212* nonsense loss of function - predicted ARID1A Q1212* results in a premature truncation of the Arid1a protein at amino acid 1212 of 2285 (UniProt.org). Q1212* has not been characterized, however, due to the effects of truncation mutations downstream of Q1212 (PMID: 26069190, PMID: 29736026), Q1212* is predicted to lead to a loss of Arid1a protein function.
Q1479* nonsense loss of function - predicted ARID1A Q1479* results in a premature truncation of the Arid1a protein at amino acid 1479 of 2285 (UniProt.org). Q1479* has not been characterized, however, due to the effects of truncation mutations downstream of Q1479 (PMID: 26069190, PMID: 29736026), Q1479* is predicted to lead to a loss of Arid1a protein function.
Q1519fs frameshift loss of function - predicted ARID1A Q1519fs results in a change in the amino acid sequence of the Arid1a protein beginning at aa 1519 of 2285, likely resulting in premature truncation of the functional protein (UniProt.org). Q1519fs has not been characterized, however, because other truncation mutations downstream of Q1519 are inactivating (PMID: 26069190), Q1519fs is predicted to lead to a loss of Arid1a protein function.
Q1631* nonsense loss of function - predicted ARID1A Q1631* results in a premature truncation of the Arid1a protein at amino acid 1631 of 2285 (UniProt.org). Q1631* has not been characterized, however, due to the effects of truncation mutations downstream of Q1631 (PMID: 26069190, PMID: 29736026), Q1631* is predicted to lead to a loss of Arid1a protein function.
Q1741* nonsense loss of function - predicted ARID1A Q1741* results in a premature truncation of the Arid1a protein at amino acid 1741 of 2285 (UniProt.org). Q1741* has not been characterized, however, due to the effects of truncation mutations downstream of Q1741 (PMID: 26069190, PMID: 29736026), Q1741* is predicted to lead to a loss of Arid1a protein function.
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).
Q515* nonsense loss of function - predicted ARID1A Q515* results in a premature truncation of the Arid1a protein at amino acid 515 of 2285 (UniProt.org). Q515* has not been characterized, however, because other truncation mutations downstream of Q515 are inactivating (PMID: 26069190), Q515* is predicted to lead to a loss of Arid1a protein function.
R1446* nonsense loss of function - predicted ARID1A R1446* results in a premature truncation of the Arid1a protein at amino acid 1446 of 2285 (UniProt.org). R1446* has not been characterized, however, due to the effects of truncation mutations downstream of R1446 (PMID: 26069190, PMID: 29736026), R1446* is predicted to lead to a loss of Arid1a protein function.
R1528* nonsense loss of function - predicted ARID1A R1528* results in a premature truncation of the Arid1a protein at amino acid 1528 of 2285 (UniProt.org). R1528* has not been characterized, however, due to the effects of truncation mutations downstream of R1528 (PMID: 26069190, PMID: 29736026), R1528* is predicted to lead to a loss of Arid1a protein function.
R1721* nonsense loss of function - predicted ARID1A R1721* results in a premature truncation of the Arid1a protein at amino acid 1721 of 2285 (UniProt.org). R1721* has not been characterized, however, due to the effects of truncation mutations downstream of R1721 (PMID: 26069190, PMID: 29736026), R1721* is predicted to lead to a loss of Arid1a protein function.
R1721fs frameshift loss of function - predicted ARID1A R1721fs results in a change in the amino acid sequence of the Arid1a protein beginning at aa 1721 of 2285, likely resulting in premature truncation of the functional protein (UniProt.org). R1721fs has not been characterized, however, due to the effects of truncation mutations downstream of R1721 (PMID: 26069190, PMID: 29736026), R1721fs is predicted to lead to a loss of Arid1a protein function.
R1722* nonsense loss of function - predicted ARID1A R1722* results in a premature truncation of the Arid1a protein at amino acid 1722 of 2285 (UniProt.org). R1722* has not been characterized, however, due to the effects of truncation mutations downstream of R1722 (PMID: 26069190, PMID: 29736026), R1722* is predicted to lead to a loss of Arid1a protein function.
S1248* nonsense loss of function - predicted ARID1A S1248* results in a premature truncation of the Arid1a protein at amino acid 1248 of 2285 (UniProt.org). S1248* has not been characterized, however, due to the effects of truncation mutations downstream of S1248 (PMID: 26069190, PMID: 29736026), S1248* is predicted to lead to a loss of Arid1a protein function.
V1561fs frameshift loss of function - predicted ARID1A V1561fs results in a change in the amino acid sequence of the Arid1a protein beginning at aa 1561 of 2285, likely resulting in premature truncation of the functional protein (UniProt.org). V1561fs has not been characterized, however, due to the effects of truncation mutations downstream of V1561 (PMID: 26069190, PMID: 29736026), V1561fs is predicted to lead to a loss of Arid1a protein function.
W1545* nonsense loss of function - predicted ARID1A W1545* results in a premature truncation of the Arid1a protein at amino acid 1545 of 2285 (UniProt.org). W1545* has not been characterized, however, due to the effects of truncation mutations downstream of W1545 (PMID: 26069190, PMID: 29736026), W1545* is predicted to lead to a loss of Arid1a protein function.
W1670* nonsense loss of function - predicted ARID1A W1670* results in a premature truncation of the Arid1a protein at amino acid 1670 of 2285 (UniProt.org). W1670* has not been characterized, however, due to the effects of truncation mutations downstream of W1670 (PMID: 26069190, PMID: 29736026), W1670* is predicted to lead to a loss of Arid1a protein function.
Y551Tfs*68 frameshift loss of function - predicted ARID1A Y551Tfs*68 indicates a shift in the reading frame starting at amino acid 551 and terminating 68 residues downstream causing a premature truncation of the 2285 amino acid Arid1a protein (UniProt.org). Y551Tfs*68 has not been characterized, however, because other truncation mutations downstream of Y551 are inactivating (PMID: 26069190), Y551Tfs*68 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 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 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 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 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 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
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 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 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