Targeting class I HDACs suppresses oncogenic vulnerabilities and potentiates KRAS/MAPK pathway inhibitors in KRAS-mutant cancers

作者：Kexin Yang, Xiaolong Qin, Yafang Wang, Wenzhong Yan, Mingyue Yao, Chengcheng Yu, Chuwei Yu, Shangxuan Shi, Yu Zhao, Lina Zhou, Cheng Li, Xiangjun Meng, Jianjun Cheng, Chengying Xie · 发表于：Journal of Advanced Research · 年份：2026 · DOI：10.1016/j.jare.2026.02.013 · 研究领域：Histone Deacetylase Inhibitors Research、Protein Degradation and Inhibitors、Angiogenesis and VEGF in Cancer

• Class I HDACi exhibit potent efficacy in various KRAS-mutant tumor models. • Class I HDACi restore wild-type p53 function and suppress YAP-MYC oncogenic axis. • YAP-driven MYC signaling and TGF-β pathway are crucial for mediating resistance to KRAS inhibitors. • Targeting class I HDACs potentiates the effect of KRAS/MAPK inhibitors and overcomes resistance. • IHCH9033 impairs PDAC metastatic progress and NSCLC brain metastasis by TGF-β pathway inhibition. KRAS mutations are prevalent in pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC) and non-small-cell lung cancer (NSCLC), characterized by poor outcomes due to limited therapies and drug resistance. Histone deacetylase inhibitors (HDACi) are effective in hematological malignancies but show limited efficacy against solid tumors with unknown mechanism, significantly restricting their clinical applications. This study aimed to evaluate the efficacy of class I HDACi in KRAS-mutant cancers, particularly in overcoming KRAS inhibitor (KRASi) resistance, and to elucidate the associated mechanisms. The effects of class I HDACi on tumor growth and metastasis, alone or combined with KRAS/MAPK inhibitors, were assessed in KRAS-mutant tumor models. Transcriptome and acetylome analyses were used to identify key effectors, while cell functional assays like flow cytometry, chromatin immunoprecipitation, and immunofluorescence explored how class I HDACi induced cell death and combated KRASi resistance. Class I HDACi, especia...