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3D epigenomic remodelling mediated by Foxa1 drives gemcitabine resistance in pancreatic cancer

Xuelong Wang1, Yizhi Cao2, Jiangning Gu3

  • 1Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine & Ruijin-Hainan Hospital, Shanghai Jiao Tong University School of Medicine (Hainan Boao Research Hospital), Shanghai, 200025, China; Lingang Laboratory, Shanghai, 200031, China.

Cancer Letters
|July 15, 2026
PubMed

Insights

Foxa1 drives gemcitabine resistance in pancreatic cancer by reprogramming enhancers. BET inhibitors like AZD5153 combined with gemcitabine overcome this resistance by targeting Foxa1, restoring drug sensitivity.

Area of Science:

  • Cancer Biology
  • Epigenetics
  • Genomics

Background:

  • Gemcitabine is a key treatment for pancreatic ductal adenocarcinoma (PDAC).
  • Drug resistance limits gemcitabine efficacy in PDAC.
  • The epigenomic mechanisms driving gemcitabine resistance are not fully understood.

Purpose of the Study:

  • To identify key regulators of gemcitabine resistance in PDAC.
  • To elucidate the epigenomic mechanisms underlying gemcitabine resistance.
  • To explore therapeutic strategies targeting identified resistance mechanisms.

Main Methods:

  • Multi-omics analysis (genomics, epigenomics) to identify regulatory factors.
  • Chromatin accessibility assays (ATAC-seq) and ChIP-seq for H3K27ac and Foxa1.
  • Cell-derived xenograft (CDX) models to test therapeutic interventions.
  • Pharmacological inhibition of BET proteins.

Main Results:

  • Foxa1 identified as a master regulator of gemcitabine resistance.
  • Foxa1 drives super-enhancer (SE) reprogramming and 3D genome alterations, activating resistance genes (Rrm1, Cdadc1).
  • USP7-mediated deubiquitination stabilizes Foxa1, sustaining the resistant epigenome.
  • Genetic ablation of Foxa1 or SEs resensitizes cells to gemcitabine.
  • BET inhibitors (AZD5153) combined with gemcitabine show potent tumor suppression in CDX models.

Conclusions:

  • Foxa1-orchestrated enhancer reprogramming is a critical mechanism of gemcitabine resistance in PDAC.
  • Targeting Foxa1-mediated epigenetic alterations with BET inhibitors offers a promising therapeutic strategy.
  • Combination therapy with gemcitabine and BET inhibitors can overcome drug resistance and restore treatment efficacy in PDAC.
Keywords:
3D genomeFoxa1Gemcitabine resistancePancreatic cancerSuper-enhancer

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