Targeting ARID1A mutations in cancer

Genes encoding SWI/SNF chromatin remodeling complex subunits are collectively mutated in approximately 20% of human cancers. ARID1A is a SWI/SNF subunit gene whose protein product binds DNA. ARID1A gene alterations result in loss of function. It is the most commonly mutated member of the SWI/SNF complex, being aberrant in -6% of cancers overall, including ovarian clear cell cancers (-45% of patients) and uterine endometrioid cancers (-37%). ARID1A has a crucial role in regulating gene expression that drives oncogenesis or tumor suppression. In particular, ARID1A participates in control of the PI3K/AKT/mTOR pathway, immune responsiveness to cancer, EZH2 methyltransferase activity, steroid receptor modulation, DNA damage checkpoints, and regulation of p53 targets and KRAS signaling. A variety of compounds may be of benefit in ARID1Aaltered cancers: immune checkpoint blockade, and inhibitors of mTOR, EZH2, histone deacetylases, ATR and/or PARP. ARID1A alterations may also mediate resistance to platinum chemotherapy and estrogen receptor degraders/modulators.

Automated summary

Mutations in ARID1A, a subunit gene of the SWI/SNF chromatin remodeling complex, are common in various cancers and play a crucial role in regulating gene expression related to oncogenesis and tumor suppression. Targeting ARID1A-altered cancers may involve a combination of immune checkpoint blockade and inhibitors of various pathways.ARID1A alterations may also mediate resistance to specific chemotherapies and hormone therapies.