ARID1B is a specific vulnerability in ARID1A-mutant cancers

Abstract

Summary Recent studies have revealed that ARID1A is frequently mutated across a wide variety of human cancers and also has bona fide tumor suppressor properties. Consequently, identification of vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. Here, using a broad screening approach, we identify ARID1B, a related but mutually exclusive homolog of ARID1A in the SWI/SNF chromatin remodeling complex, as the number one gene preferentially required for the survival of ARID1A-mutant cancer cell lines. We show that loss of ARID1B in ARID1A-deficient backgrounds destabilizes SWI/SNF and impairs proliferation. Intriguingly, we also find that ARID1A and ARID1B are frequently co-mutated in cancer, but that ARID1A-deficient cancers retain at least one ARID1B allele. These results suggest that loss of ARID1A and ARID1B alleles cooperatively promotes cancer formation but also results in a unique functional dependence. The results further identify ARID1B as a potential therapeutic target for ARID1A-mutant cancers.

Targeting p300 Addiction inCBP-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation ofMYCExpression

“…The frequency and prevalence of mutations that inactivate chromatin modifi ers in a wide range of human cancers indicate that such mutations are driver alterations that cause loss of tumorsuppressive functions ( 14 ). The promise of paralog targeting in precision cancer medicine has been further validated by the addition of the strategy described here to the previously established repertoire, e.g., the use of SMARCA2/BRMATPase inhibition against SMARCA4/BRG1 -defi cient cancers and ARID1B inhibition against ARID1A-defi cient cancers [19][20][21][22][23]. Thus, the paralog targeting strategy should be applicable to a considerable fraction of human cancers.…”

“…These fi ndings were subsequently supported by several studies, including some that employed genome-wide RNA interference scanning (20)(21)(22). Recently, this concept has been extended to ARID1A -defi cient cancers ( 23 ). Based on successful precision medicine approaches that have target-activated oncogene products, paralog targeting strategies must meet the following criteria to be successfully translated to the clinic.…”

Glioma tumor suppressor candidate region gene 1 (GLTSCR1) and its paralog GLTSCR1-like form SWI/SNF chromatin remodeling subcomplexes

“…The different BAF complexes containing these two paralogs share many of their genomic targets; however, they also bind unique genomic targets and deletions are non-synonymous for gene regulation (20). ARID1A is the most commonly mutated SWI/SNF subunit in cancer, due to transcriptional functions that are non-redundant with ARID1B (21,22); however, cancers with deletions in ARID1A are dependent on ARID1B for viability (23) due to redundant, essential functions at enhancers (22). Additionally, homologous complexes can display transcriptionally antagonistic roles, as has been observed for ARID1A and ARID2-containing complexes at specific gene targets (8,20,24).…”

Aberrant chromatin remodeling in gynecological cancer (Review)

“…ARID1B has recently been identified as an ARID1A homolog (63). In cells with an ARID1A deficit, ARID1B is independently expressed and its proliferation is enhanced, which suggests that ARID1A and ARID1B may interact in promoting carcinogenesis.…”