ANP32A-mediated histone 3 K27 acetylation is essential for sotorasib activity in KRAS-mutant non-small cell lung cancer.

Drug resistance is a major challenge for the target therapy of KRAS-mutant non-small cell lung cancer (NSCLC). Here, we observe that ANP32A is tightly associated with KRAS-mutant NSCLC and serves as an unfavorable prognosis factor. ANP32A deficiency impaired cell proliferation, migration, invasion, and cell cycle progression and induced sotorasib (Sot) resistance in KRAS-mutant NSCLC cells, which were reversed by ANP32A reoverexpression in ANP32A-deficient cells. Mechanistically, ANP32A deficiency impaired histone 3 acetylation at lysine 27 (H3K27Ac). Particularly, ANP32A deficiency reduced H3K27Ac of the YEATS4 gene promoter and downregulated YEATS4 expression. ANP32A also interacted with YEATS4 and promoted its binding to H3K27Ac. Furthermore, YEATS4 overexpression partially restored ANP32A deficiency-impaired cell proliferation, H3K27Ac, and Sot sensitivity. Most importantly, trichostatin A mimicked the effect of ANP32A, which restored YEATS4 expression, antagonized Sot resistance, and resensitized ANP32A-deficient cells to Sot in vitro and in vivo, possibly by reactivating the p53 pathway. Our study identifies a new epigenetic mechanism involving the ANP32A that promotes KRAS-mutant lung cancer growth and affects Sot activity. The combination of Sot and histone deacetyltransferase inhibitors could be an effective treatment for KRAS-mutant lung cancer. ANP32A may serve as a biomarker for Sot treatment.