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Updated: Jul 11, 2025

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STK11 loss leads to YAP1-mediated transcriptional activation in human KRAS-driven lung adenocarcinoma cell lines

Sean M Lenahan1, Hailey M Sarausky1, Paula Deming2,3

  • 1Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA.

Cancer Gene Therapy
|November 15, 2023
PubMed

Insights

Serine Threonine Kinase 11 (STK11) loss impairs anti-PD-1 therapy in KRAS-driven lung cancer. STK11 loss activates YAP1 signaling, increasing immune-evasive cytokines and potentially offering a therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunotherapy

Background:

  • Serine Threonine Kinase 11 (STK11) loss of function is linked to resistance against anti-PD-1 immunotherapy in KRAS-driven lung adenocarcinoma (LUAD).
  • The precise molecular mechanisms behind this resistance are not well understood, representing a significant gap in lung cancer research.

Purpose of the Study:

  • To investigate the molecular consequences of STK11 loss in KRAS-driven LUAD.
  • To identify potential therapeutic strategies to overcome anti-PD-1 resistance associated with STK11 deficiency.

Main Methods:

  • STK11 was knocked out (KO) in human LUAD cell lines.
  • Whole transcriptome analysis was performed to identify gene expression changes.
  • Pathway enrichment analysis and YAP1 perturbation were used to validate findings.

Main Results:

  • STK11 loss led to differential gene expression, notably activating the HIPPO/YAP1 signaling axis.
  • Upregulation of immune-evasion cytokines, including IL-6, CXCL8, and CXCL2, was observed.
  • YAP1 perturbation partially restored an STK11-competent gene expression profile.

Conclusions:

  • STK11 loss promotes YAP1-mediated transcriptional activation and upregulates immune-suppressive cytokines in LUAD.
  • Targeting YAP1 may be a viable strategy to enhance anti-PD-1 therapy efficacy in STK11-null LUAD by promoting a "hot" tumor immune microenvironment.

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