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STAT3 sustains tumorigenicity following mutant KRAS ablation

Stephen D'Amico1,2, Varvara Kirillov1, Jingxuan Liu3,4

  • 1Department of Microbiology and Immunology, Stony Brook University, Stony Brook, NY, 11794, USA.

EMBO Reports
|August 26, 2025
PubMed

Insights

STAT3 supports tumor growth after KRAS inactivation in pancreatic cancer. Blocking both STAT3 and KRAS disrupts cancer cell identity, impairing tumor growth and promoting clearance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Oncogenic KRAS mutations are drivers of lethal human cancers.
  • KRAS inactivation yields variable outcomes and resistance, with underlying mechanisms unclear.
  • Understanding resistance is crucial for effective cancer therapy.

Purpose of the Study:

  • To investigate the role of STAT3 in tumor persistence following KRAS depletion.
  • To elucidate the mechanisms by which STAT3 supports tumorigenicity in KRAS-ablated cancers.
  • To identify vulnerabilities in KRAS-mutant cancers upon KRAS inhibition.

Main Methods:

  • CRISPR-mediated ablation of mutant KRAS in pancreatic ductal adenocarcinoma models.
  • Functional assays to assess STAT3 dependency in surviving cancer cells.
  • Transcriptional profiling to identify disrupted core programs.
  • In vivo studies in mice to evaluate tumor growth and immune response.

Main Results:

  • Cancer cells surviving KRAS ablation depend on STAT3 for tumorigenicity.
  • Combined loss of KRAS and STAT3 disrupts a critical cancer cell transcriptional program.
  • Impaired tumor growth and enhanced immune rejection observed in double-ablated models.
  • STAT3 enforces malignant identity in KRAS-ablated tumors, promoting persistence.

Conclusions:

  • STAT3 acts as a critical enforcer of oncogenic identity in KRAS-ablated tumors.
  • The STAT3 transcriptional program maintains cancer cell malignancy post-KRAS inactivation.
  • Targeting STAT3 represents a key vulnerability in KRAS-driven cancers.
  • This study reveals a novel therapeutic strategy for KRAS-mutant cancers.
Keywords:
KRASOncogene DependencePancreatic CancerSTAT3

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