2. Academic Validation
  3. Targeting class I HDACs suppresses oncogenic vulnerabilities and potentiates KRAS/MAPK pathway inhibitors in KRAS-mutant cancers

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

  • J Adv Res. 2026 Feb 13:S2090-1232(26)00144-X. doi: 10.1016/j.jare.2026.02.013.
Kexin Yang 1,  Xiaolong Qin 2,  Yafang Wang 3,  Wenzhong Yan 4,  Mingyue Yao 5,  Chengcheng Yu 5,  Chuwei Yu 5,  Shangxuan Shi 2,  Yu Zhao 2,  Lina Zhou 2,  Cheng Li 2,  Xiangjun Meng 6,  Jianjun Cheng 7,  Chengying Xie 8
Affiliations

Affiliations

  • 1 Lingang Laboratory, Shanghai 201101, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 2 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.
  • 3 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.
  • 4 iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • 5 Lingang Laboratory, Shanghai 201101, China.
  • 6 Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China; Center for Digestive Diseases Research and Clinical Translation of Shanghai Jiao Tong University, Shanghai 200001, China; Shanghai Key Laboratory of Gut Microecology and Associated Major Diseases Research, Shanghai 200001, China. Electronic address: [email protected].
  • 7 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; iHuman Institute, ShanghaiTech University, Shanghai 201210, China. Electronic address: [email protected].
  • 8 Lingang Laboratory, Shanghai 201101, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China. Electronic address: [email protected].
PMID: 41692243 DOI: 10.1016/j.jare.2026.02.013
Abstract

Introduction: 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.

Objectives: 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.

Methods: 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.

Results: 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 KRASG12C-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.

Conclusion: 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.

Keywords

Class I HDACs; IHCH9033; KRAS; MYC; YAP; p53.

Figures
Products