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Updated: Jul 15, 2025

Mimicking and Manipulating Pancreatic Acinar-to-Ductal Metaplasia in 3-dimensional Cell Culture
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Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer

Jincheng Han1, Jiaqian Xu2, Yonghong Liu1

  • 1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 USA.

Genes & Development
|September 29, 2023
PubMed

Insights

Cancer-associated fibroblasts (CAFs) promote resistance to KRAS inhibitors in pancreatic cancer by activating NRG1 signaling. Targeting this pathway can overcome resistance and improve treatment efficacy for pancreatic ductal adenocarcinoma (PDAC) patients.

Area of Science:

  • Oncology
  • Cancer Biology
  • Molecular Therapeutics

Background:

  • Activating KRAS mutations (KRAS*) are key drivers of pancreatic ductal adenocarcinoma (PDAC) growth and metabolism.
  • KRAS* inhibitors show initial efficacy but are often followed by tumor recurrence due to resistance mechanisms.

Purpose of the Study:

  • To investigate the role of cancer-associated fibroblasts (CAFs) in mediating resistance to KRAS* inhibitors in PDAC.
  • To identify the specific molecular pathways by which CAFs contribute to KRAS* inhibitor bypass.

Main Methods:

  • Utilized human and murine PDAC models.
  • Investigated the effects of genetic and pharmacological inhibition of KRAS*, ERBB2/3, and NRG1.
  • Assessed the synergistic effects of combination therapies.

Main Results:

  • KRAS* inhibition upregulated ERBB2 and ERBB3 expression in cancer cells.
  • Cancer cells exploited CAF-derived NRG1 via ERBB2/3 signaling for KRAS*-independent growth.
  • Inhibition of ERBB2/3 or NRG1 abolished KRAS* bypass and synergized with KRAS* inhibitors.

Conclusions:

  • CAFs contribute to KRAS* inhibitor resistance in PDAC through paracrine NRG1/ERBB2/3 signaling.
  • Targeting the CAF-NRG1-ERBB2/3 axis represents a viable therapeutic strategy to enhance KRAS* inhibitor efficacy in PDAC.
Keywords:
ERBB3NRG1cancer-associated fibroblastsoncogenic KRAS bypasspancreas cancerreceptor tyrosine kinasetumor microenvironment

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