Inhibiting PLK1, a direct upstream target of CDC25C, or CDC25C itself recapitulated the synthetic lethality phenotype in ARID1A-deficient cells, further supporting the idea that the AURKA–PLK1–CDC25C axis is a key pathway activated in ARID1A-deficient CRC and that it could serve as a therapeutic target. Here, ARID1A is linked to colorectal carcinoma.