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

• 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, especially the novel inhibitor IHCH9033, demonstrated desirable pharmacokinetic properties and strong efficacy in various KRAS-mutant tumor xenografts. Mechanistically, class I HDACi induced p53 acetylation, restoring its wild-type function, and c-Myc acetylation, promoting its proteasomal degradation, collectively leading to oxidative stress, DNA damage and apoptosis. Further study illustrated the regulatory effect of p53 on YAP/TAZ activity. Critically, IHCH9033 surmounted KRASi resistance by suppressing YAP-c-Myc axis while also acting synergistically with KRAS/MAPK inhibitors to repress MAPK and other oncogenic signaling. This combination robustly enhanced tumor suppression in both KRASi-sensitive and −resistant cell xenografts, including a KRAS G12C -mutant CRC patient-derived xenograft model. Notably, IHCH9033 exhibited brain bioavailability and reduced metastatic progression in a NSCLC brain metastasis model and an orthotopic PDAC model by blocking the YAP-TGF-β crosstalk. Targeting class I HDACs, alone or combined with KRAS/MAPK inhibitors, represents a promising therapeutic strategy that concurrently disrupts both epigenetic and oncogenic pathways to treat KRAS-mutant cancers and overcome resistance, warranting clinical evaluation.