This is the first study investigating the unique combination of USP1 inhibitor (KSQ‐4279) and traditional chemotherapy to overcome MDR, which disclosed ABCB1, ABCG2, and ABCC1 as the new targets of KSQ‐4279 independent of its acknowledged target USP1, and hinted a novel combination strategy in clinic to treat cancer patients bearing drug‐refractory tumors. The gene discussed is ABCG2; the disease is cancer.