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Intratumor heterogeneity in KRAS signaling shapes treatment resistance

Oleksi Petrenko1, Varvara Kirillov1, Stephen D'Amico1

  • 1Department of Microbiology and Immunology, Stony Brook University, Stony Brook, NY, USA.

Iscience
|February 3, 2025
PubMed

Insights

Pancreatic cancer cells show varied KRAS dependency. Targeting KRAS alone spares some cells, but combination immunotherapy effectively regresses tumors in models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • KRAS mutations drive aggressive cancers, including pancreatic ductal adenocarcinoma (PDAC).
  • Targeting KRAS is a promising strategy, but resistance mechanisms, potentially linked to tumor heterogeneity, are a concern.

Purpose of the Study:

  • To investigate intratumor heterogeneity in PDAC concerning KRAS dependency and treatment resistance.
  • To understand how different cell populations within a tumor respond to KRAS inhibition.

Main Methods:

  • Integrated analysis of single-cell and bulk RNA sequencing data from PDAC tumors.
  • Characterization of cell populations based on gene expression related to KRAS signaling, growth, and differentiation.

Main Results:

  • PDAC tumors exhibit significant intratumor heterogeneity, with distinct cell populations displaying varying degrees of KRAS dependency.
  • Selective KRAS targeting inhibited tumor cells with high RAS/MAPK activity but spared those with low RAS signaling.
  • Combination immunotherapy achieved durable tumor regression in preclinical models.

Conclusions:

  • Intratumor heterogeneity in KRAS dependency is a critical factor in PDAC treatment resistance.
  • Targeting KRAS alone is insufficient due to resistant cell subsets.
  • Combination immunotherapy represents a viable strategy for durable tumor regression in PDAC.
Keywords:
CancerCell biologyOmics

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