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LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers

Author

Listed:
  • Chendi Li

    (Massachusetts General Hospital Cancer Center
    Massachusetts General Hospital and Harvard Medical School)

  • Mohammed Usman Syed

    (Massachusetts General Hospital Cancer Center)

  • Anahita Nimbalkar

    (Massachusetts General Hospital Cancer Center)

  • Yi Shen

    (Massachusetts General Hospital Cancer Center)

  • Melissa D. Vieira

    (Massachusetts General Hospital Cancer Center)

  • Cameron Fraser

    (Harvard T.H. Chan School of Public Health
    Harvard T.H. Chan School of Public Health)

  • Zintis Inde

    (Harvard T.H. Chan School of Public Health
    Harvard T.H. Chan School of Public Health)

  • Xingping Qin

    (Harvard T.H. Chan School of Public Health
    Harvard T.H. Chan School of Public Health)

  • Jian Ouyang

    (Massachusetts General Hospital Cancer Center
    Medical University of South Carolina)

  • Johannes Kreuzer

    (Massachusetts General Hospital Cancer Center
    Massachusetts General Hospital and Harvard Medical School)

  • Sarah E. Clark

    (Massachusetts General Hospital Cancer Center)

  • Grace Kelley

    (Massachusetts General Hospital Cancer Center)

  • Emily M. Hensley

    (Massachusetts General Hospital Cancer Center)

  • Robert Morris

    (Massachusetts General Hospital Cancer Center)

  • Raul Lazaro

    (Amgen Inc.)

  • Brian Belmonte

    (Amgen Inc.)

  • Audris Oh

    (Massachusetts General Hospital Cancer Center)

  • Makeba Walcott

    (Massachusetts General Hospital Cancer Center)

  • Christopher S. Nabel

    (Massachusetts General Hospital Cancer Center
    Massachusetts Institute of Technology)

  • Sean Caenepeel

    (Amgen Inc.)

  • Anne Y. Saiki

    (Amgen Inc.)

  • Karen Rex

    (Amgen Inc.)

  • J. Russell Lipford

    (Amgen Inc.)

  • Rebecca S. Heist

    (Massachusetts General Hospital Cancer Center
    Massachusetts General Hospital and Harvard Medical School)

  • Jessica J. Lin

    (Massachusetts General Hospital Cancer Center
    Massachusetts General Hospital and Harvard Medical School)

  • Wilhelm Haas

    (Massachusetts General Hospital Cancer Center)

  • Kristopher Sarosiek

    (Harvard T.H. Chan School of Public Health
    Harvard T.H. Chan School of Public Health
    Harvard Medical School)

  • Paul E. Hughes

    (Amgen Inc.)

  • Aaron N. Hata

    (Massachusetts General Hospital Cancer Center
    Massachusetts General Hospital and Harvard Medical School)

Abstract

The efficacy of molecularly targeted therapies may be limited by co-occurring mutations within a tumor. Conversely, these alterations may confer collateral vulnerabilities that can be therapeutically leveraged. KRAS-mutant lung cancers are distinguished by recurrent loss of the tumor suppressor STK11/LKB1. Whether LKB1 modulates cellular responses to therapeutic stress seems unknown. Here we show that in LKB1-deficient KRAS-mutant lung cancer cells, inhibition of KRAS or its downstream effector MEK leads to hyperactivation of JNK due to loss of NUAK-mediated PP1B phosphatase activity. JNK-mediated inhibitory phosphorylation of BCL-XL rewires apoptotic dependencies, rendering LKB1-deficient cells vulnerable to MCL-1 inhibition. These results uncover an unknown role for LKB1 in regulating stress signaling and mitochondrial apoptosis independent of its tumor suppressor activity mediated by AMPK and SIK. Additionally, our study reveals a therapy-induced vulnerability in LKB1-deficient KRAS-mutant lung cancers that could be exploited as a genotype-informed strategy to improve the efficacy of KRAS-targeted therapies.

Suggested Citation

  • Chendi Li & Mohammed Usman Syed & Anahita Nimbalkar & Yi Shen & Melissa D. Vieira & Cameron Fraser & Zintis Inde & Xingping Qin & Jian Ouyang & Johannes Kreuzer & Sarah E. Clark & Grace Kelley & Emily, 2025. "LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58753-y
    DOI: 10.1038/s41467-025-58753-y
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