Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response

Abstract

Chromatin remodeling is an essential cellular process for organizing chromatin structure into either open or close configuration at specific chromatin locations by orchestrating and modifying histone complexes. This task is responsible for fundamental cell physiology including transcription, DNA replication, methylation, and damage repair. Aberrations in this activity have emerged as epigenomic mechanisms in cancer development that increase tumor clonal fitness and adaptability amidst various selection pressures. Inactivating mutations in AT-rich interaction domain 1A (ARID1A), a gene encoding a large nuclear protein member belonging to the SWI/SNF chromatin remodeling complex, result in its loss of expression. ARID1A is the most commonly mutated chromatin remodeler gene, exhibiting the highest mutation frequency in endometrium-related uterine and ovarian carcinomas. As a tumor suppressor gene, ARID1A is essential for regulating cell cycle, facilitating DNA damage repair, and controlling expression of genes that are essential for maintaining cellular differentiation and homeostasis in non-transformed cells. Thus, ARID1A deficiency due to somatic mutations propels tumor progression and dissemination. The recent success of PARP inhibitors in treating homologous recombination DNA repair-deficient tumors has engendered keen interest in developing synthetic lethality-based therapeutic strategies for ARID1A-mutated neoplasms. In this review, we summarize recent advances in understanding the biology of ARID1A in cancer development, with special emphasis on its roles in DNA damage repair. We also discuss strategies to harness synthetic lethal mechanisms for future therapeutics against ARID1A-mutated cancers.

Targeting ARID1A-Deficient Cancers: An Immune-Metabolic Perspective

“…Recent advances, including CRISPR/Cas9-based gene editing, have made possible systematic screens for synthetic lethal targets in human cancers harboring mutations of tumor suppressor, such as ARID1A. Ever since the discovery as a tumor suppressor for ARID1A, synthetic lethal phenotypes have been uncovered in ARID1A-deficient cells when treated with PARP inhibitors, ATR inhibitors, EZH2 inhibitors, and other emerging agents [ 13 ].…”

“…Given the emerging roles of ARID1A in the DNA damage response [ 13 ], accumulating evidence has enhanced our understanding of the biological role of ARID1A, offering new mechanisms for synthetic lethality-based targeting of ARID1A-inactivated cancers, such as inhibition of PARP [ 71 , 72 ] and ATR [ 73 ]. Recently, Wang et al reported that ARID1A-mutated/deficient tumors exhibited high expression of Chk2, a DNA damage checkpoint kinase downstream of ATM, through modulating autoubiquitination of the E3-ligase RNF8 and thereby reducing RNF8-mediated Chk2 degradation.…”

“…Functional genomics studies have revealed that genes encoding subunits of SWI/SNF are collectively mutated in 20–25% of all human malignancies, among which ARID1A is the most frequently mutated subunit in a broad spectrum of human cancers [ 11 ] ( Table 1 ). Recent mechanistic studies have further demonstrated a crucial role for ARID1A in the regulation of gene expression that drives oncogenesis or tumor suppression [ 12 , 13 , 14 ]. The mechanism of action of ARID1A in cancer has been mainly attributed to its chromatin remodeling function within the SWI/SNF complex, leading to aberrant cell proliferation, differentiation and apoptosis that have tumorigenic consequences [ 11 ].…”

The Role of Genetic Mutations in Mitochondrial-Driven Cancer Growth in Selected Tumors: Breast and Gynecological Malignancies

“…Different subunits are associated with different tumors: for example, SMARC1 loss is seen in atypical teratoid/rhabdoid tumors (ATRTs), among others [380,381], whereas AIRD1A loss has been described in endometrioid EC (~40%), endometrioid (~30%), clear-cell (46-57%) OCs, etc., with up to ~20% of all human cancers harboring AIRD1A-inactivating mutations [337,372,[382][383][384][385]. In addition, the loss of ARID1A has been demonstrated in patient samples with atypical endometriotic lesions contiguous to clear-cell OC, raising the possibility that the loss of ARID1A may contribute to an early cancer-promoting event in endometriosis that leads to clear-cell OC [337].…”

“…Additionally, in ~13% of BCs, there is mostly a loss of heterozygosity of ARID1A, resulting in reduced protein expression and a more aggressive cancer phenotype [386]. In various tumors, ARID1A loss is mainly due to ARID1A promoter hypermethylation, but it also can be due to inactivating mutations or in-frame insertions/deletions [382,386]. In some cases, post-translational changes lead to the loss of the ARID1A protein.…”