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Updated: Jan 17, 2026

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KRAS Inhibition Activates an Actionable CD24 "Do Not Eat Me" Signal in Pancreatic Cancer

Yongkun Wei1, Minghui Liu1, Er-Yen Yen2,3

  • 1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Cancer Research
|September 18, 2025
PubMed

Insights

KRASG12C inhibitors show limited benefit in pancreatic cancer. Blocking the CD24 "do not eat me" signal enhances immune cell targeting of cancer cells, improving treatment efficacy for KRAS-driven pancreatic ductal adenocarcinoma.

Area of Science:

  • Oncology
  • Cancer Biology
  • Immunology

Background:

  • KRASG12C inhibitors offer modest clinical benefit for pancreatic ductal adenocarcinoma (PDAC).
  • Understanding and overcoming resistance mechanisms to KRASG12C inhibitors is critical for improving patient outcomes.
  • Developing autochthonous models is key to studying KRAS-driven PDAC biology and therapeutic resistance.

Purpose of the Study:

  • To investigate the biological functions of KRASG12C and identify bypass mechanisms in PDAC.
  • To evaluate the efficacy of KRASG12C inhibitors in a relevant preclinical model.
  • To uncover adaptive resistance mechanisms and potential therapeutic targets.

Main Methods:

  • Development of an autochthonous KRASG12C-driven PDAC mouse model.
  • Comparison with a KRASG12D-driven PDAC model.
  • Treatment with KRASG12C inhibitors and subsequent immunoprofiling.
  • Assessment of CD24 expression and blockade effects on tumor immunity and response.

Main Results:

  • The KRASG12C model exhibited slower tumor growth but similar features to KRASG12D models.
  • KRASG12C inhibitors induced a "hot" tumor immune microenvironment with modest clinical impact.
  • CD24, a "do not eat me" signal, was upregulated on cancer cells post-treatment.
  • CD24 blockade enhanced macrophage phagocytosis and sensitized tumors to G12Ci treatment in both KRASG12C and KRASG12D models.

Conclusions:

  • This study reveals distinct KRAS allele-specific biology in PDAC.
  • Upregulation of CD24 represents a clinically actionable adaptive resistance mechanism.
  • Targeting CD24 in combination with KRAS inhibitors may enhance therapeutic efficacy in PDAC.

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