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Updated: Jun 21, 2025

Syngeneic Mouse Orthotopic Allografts to Model Pancreatic Cancer
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Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer

Julien Dilly1,2,3, Megan T Hoffman3,4, Laleh Abbassi1,2,3

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Cancer Discovery
|July 8, 2024
PubMed

Insights

KRAS inhibitors show promise in pancreatic cancer but resistance develops. New research identifies genetic and non-genetic resistance mechanisms, supporting combination therapies for better patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • KRAS inhibitors are effective against pancreatic ductal adenocarcinoma (PDAC).
  • Acquired resistance frequently limits the clinical benefit of KRAS inhibitors in PDAC patients.
  • Understanding resistance mechanisms is crucial for improving treatment efficacy.

Purpose of the Study:

  • To elucidate the genetic and non-genetic mechanisms of acquired resistance to KRAS inhibition in PDAC.
  • To identify potential combination therapy strategies to overcome resistance.

Main Methods:

  • Analysis of patient samples with acquired resistance to KRAS inhibitors.
  • Treatment of PDAC cell lines, organoids, and KPC mouse models with KRAS inhibitors.
  • Genomic profiling (mutations, amplifications) and transcriptional analysis.
  • Evaluation of combination therapy with KRAS inhibitors and chemotherapy.

Main Results:

  • Acquired resistance involved mutations in PIK3CA and KRAS, and amplifications of KRAS, MYC, MET, EGFR, and CDK6.
  • Epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling were associated with resistance to MRTX1133.
  • Kras, Yap1, Myc, Cdk6, and Abcb1a/b amplifications and resistant transcriptional programs emerged in KPC models.
  • Mesenchymal and basal-like cell states showed increased sensitivity to KRAS inhibition.
  • Combination therapy with KRASG12D inhibition and chemotherapy improved tumor control.

Conclusions:

  • KRAS inhibition in PDAC is associated with diverse co-evolving resistance mechanisms.
  • Combination strategies, including chemotherapy, may enhance the efficacy and durability of KRAS inhibitors.
  • Identifying resistance mechanisms guides the development of improved therapeutic approaches for PDAC.

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