Fig. 5
From: Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response
Synthetic lethal partners of ARID1A deficiency. The left panel illustrates various synthetic lethal targets of ARID1A deficiency belonging to diverse cellular functions such as regulating cell cycle, DNA protection, cellular metabolism, signaling pathways, epigenetic functions, and immune checkpoint regulation. The right panel illustrates mechanisms of synthetic lethality of new targets such as PLK1 and USP9X. The deubiquitinating enzyme USP9X is transcriptionally repressed by ARID1A, whose loss upregulates USP9X. USP9X upregulates AMPK (AMP-activated protein kinase) signaling for cellular survival under glucose deprivation. Targeting AMPK with dorsomorphin (Compound C) kills the cancer cells. Similarly, inhibition of PLK1 (Polo Like Kinase 1) induces apoptosis due to uncoupled Oxidative phosphorylation (OXPHOS). AURKA (Aurora kinase A) phosphorylates CDC25C through PLK1. CDC25C checks G2/M checkpoint. Loss of AURKA results in G2/M arrest. The DNA damage response also checks CDC25C [102]. Illustration created using Biorender.com