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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	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	5	7	2015 Jul	752-67	Cancer Discov

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
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Showing 1 to 39 of 39 entries

Gene	Variant	Impact	Protein Effect	Variant Description
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	A35Gfs*76	frameshift	loss of function - predicted	ARID1A A35Gfs76 indicates a shift in the reading frame starting at amino acid 35 and terminating 76 residues downstream causing a premature truncation of the 2285 amino acid Arid1a protein (UniProt.org). A35Gfs76 has not been characterized however, due to the effects of other truncation mutations downstream of A35 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A	P65Rfs*36	frameshift	loss of function - predicted	ARID1A P65Rfs36 indicates a shift in the reading frame starting at amino acid 65 and terminating 36 residues downstream causing a premature truncation of the 2285 amino acid Arid1a protein (UniProt.org). P65Rfs36 has not been characterized however, due to the effects of other truncation mutations downstream of P65 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A	G83Wfs*28	frameshift	loss of function - predicted	ARID1A G83Wfs28 indicates a shift in the reading frame starting at amino acid 83 and terminating 28 residues downstream causing a premature truncation of the 2285 amino acid Arid1a protein (UniProt.org). G83Wfs28 has not been characterized, however, due to the effects of other truncation mutations downstream of G83 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A	P94Lfs*7	frameshift	loss of function - predicted	ARID1A P94Lfs7 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). P94Lfs7 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	P135Lfs*96	frameshift	loss of function - predicted	ARID1A P135Lfs96 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). P135Lfs96 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	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	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	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	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 P224Rfs8 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). P224Rfs8 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	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	Q268*	nonsense	loss of function - predicted	ARID1A Q268* results in a premature truncation of the Arid1a protein at amino acid 268 of 2285 (UniProt.org). Q268* has not been characterized however, due to the effects of other truncation mutations downstream of Q268 (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 G276Efs87 indicates a shift in the reading frame starting at amino acid 276 and terminating 87 residues downstream causing a premature truncation of the 2285 amino acid Arid1a protein (UniProt.org). G276Efs87 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	G277fs	frameshift	loss of function - predicted	ARID1A G277fs results in a change in the amino acid sequence of the Arid1a protein beginning at aa 277 of 2285, likely resulting in premature truncation of the functional protein (UniProt.org). G277fs has not been characterized, however, due to the effects of other truncation mutations downstream of G277 (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	Q288Pfs*112	frameshift	loss of function - predicted	ARID1A Q288Pfs112 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). Q288Pfs112 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	T292Pfs*71	frameshift	loss of function - predicted	ARID1A T292Pfs71 indicates a shift in the reading frame starting at amino acid 292 and terminating 71 residues downstream causing a premature truncation of the 2285 amino acid Arid1a protein (UniProt.org). T292Pfs71 has not been characterized, however, due to the effects of other truncation mutations downstream of T292 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A	T294Pfs*69	frameshift	loss of function - predicted	ARID1A T294Pfs69 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). T294Pfs69 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.
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	Q321Rfs*42	frameshift	loss of function - predicted	ARID1A Q321Rfs42 indicates a shift in the reading frame starting at amino acid 321 and terminating 42 residues downstream causing a premature truncation of the 2285 amino acid Arid1a protein (UniProt.org). Q321Rfs42 has not been characterized, however, due to the effects of other truncation mutations downstream of Q321 (PMID: 26069190, PMID: 29736026), is predicted to lead to a loss of Arid1a protein function.
ARID1A	A339Gfs*61	frameshift	loss of function - predicted	ARID1A A339Gfs61 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). A339Gfs61 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 A339Lfs24 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). A339Lfs24 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	S366Afs*25	frameshift	loss of function - predicted	ARID1A S366Afs25 indicates a shift in the reading frame starting at amino acid 366 and terminating 25 residues downstream causing a premature truncation of the 2285 amino acid Arid1a protein (UniProt.org). S366Afs25 has not been characterized, however, due to the effects of other truncation mutations downstream of S366 (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 Q372Afs28 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). Q372Afs28 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	Q372fs	frameshift	loss of function - predicted	ARID1A Q372fs results in a change in the amino acid sequence of the Arid1a protein beginning at aa 372 of 2285, likely resulting in premature truncation of the functional protein (UniProt.org). Q372fs 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 Q372Sfs19 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). Q372Sfs19 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	Y395*	nonsense	loss of function - predicted	ARID1A Y395* results in a premature truncation of the Arid1a protein at amino acid 395 of 2285 (UniProt.org). Y395* has not been characterized, however, due to the effects of other truncation mutations downstream of Y395 (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	Q405*	nonsense	loss of function - predicted	ARID1A Q405* results in a premature truncation of the Arid1a protein at amino acid 405 of 2285 (UniProt.org). Q405* has not been characterized, however, due to the effects of other truncation mutations downstream of Q405 (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).

Showing 1 to 39 of 39 entries

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Showing 1 to 8 of 8 entries

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ARID1A dec exp	breast cancer	conflicting	Talazoparib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Talzenna (talazoparib) 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	Talazoparib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Talzenna (talazoparib) 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	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 Talzenna (talazoparib) in ovarian cancer cells 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 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	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	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

Showing 1 to 8 of 8 entries

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