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Cancer Discov. 2015 Jul;5(7):752-67. doi: 10.1158/2159-8290.CD-14-0849. Epub 2015 Jun 11.

ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors.

Author information

1
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
3
Department of Microbiology and Molecular Genetics, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. The University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
4
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Medical Oncology, Tongji Hospital, Tongji Medical College, The Huazhong University of Science and Technology, Wuhan, P.R. China.
5
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
7
Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
8
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
9
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Medical Oncology, Tongji Hospital, Tongji Medical College, The Huazhong University of Science and Technology, Wuhan, P.R. China. gpeng@mdanderson.org.

Abstract

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.

SIGNIFICANCE:

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.

PMID:
26069190
PMCID:
PMC4497871
DOI:
10.1158/2159-8290.CD-14-0849
[Indexed for MEDLINE]
Free PMC Article

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