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Targeting class I HDACs suppresses oncogenic vulnerabilities and potentiates KRAS/MAPK pathway inhibitors in
Kexin Yang1, Xiaolong Qin2, Yafang Wang3
1Lingang Laboratory, Shanghai 201101, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
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.
Insights
Class I HDAC inhibitors show promise against KRAS-mutant cancers like pancreatic cancer and colorectal cancer, overcoming drug resistance by restoring p53 function and degrading c-Myc. This epigenetic approach warrants clinical trials.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- KRAS mutations are common in pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small-cell lung cancer (NSCLC), leading to poor prognoses.
- Histone deacetylase inhibitors (HDACi) are effective in blood cancers but limited in solid tumors, with mechanisms against KRAS-mutant cancers unclear.
Purpose of the Study:
- Evaluate class I HDAC inhibitors (HDACi) for efficacy in KRAS-mutant cancers.
- Determine if HDACi can overcome resistance to KRAS inhibitors (KRASi).
- Elucidate the molecular mechanisms underlying HDACi efficacy and resistance modulation.
Main Methods:
- Assessed class I HDACi effects on tumor growth and metastasis in KRAS-mutant models, alone and with KRAS/MAPK inhibitors.
- Utilized transcriptome and acetylome analyses to identify key molecular targets.
- Employed cell functional assays (flow cytometry, ChIP, immunofluorescence) to investigate mechanisms of cell death and KRASi resistance.
Main Results:
- Class I HDACi, particularly IHCH9033, showed strong efficacy and favorable pharmacokinetics in KRAS-mutant xenografts.
- HDACi induced p53 acetylation (restoring function) and c-Myc acetylation (promoting degradation), leading to apoptosis via oxidative stress and DNA damage.
- IHCH9033 overcame KRASi resistance by inhibiting the YAP-c-Myc axis, synergized with KRAS/MAPK inhibitors, and reduced metastasis by blocking YAP-TGF-β crosstalk.
Conclusions:
- Targeting class I HDACs offers a dual approach disrupting epigenetic and oncogenic pathways in KRAS-mutant cancers.
- Combination therapy with HDACi and KRAS/MAPK inhibitors is a promising strategy to treat KRAS-mutant cancers and overcome resistance.
- Clinical evaluation of this therapeutic strategy is warranted.
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