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

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 M. Hensley, Robert Morris, Raul Lazaro, Brian Belmonte, Audris Oh, Makeba Walcott, Christopher S. Nabel, Sean Caenepeel, Anne Y. Saiki, Karen Rex, J. Russell Lipford, Rebecca S. Heist, Jessica J. Lin, Wilhelm Haas, Kristopher Sarosiek, Paul E. Hughes and Aaron N. Hata ()
Additional contact information
Chendi Li: Massachusetts General Hospital Cancer Center
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
Zintis Inde: Harvard T.H. Chan School of Public Health
Xingping Qin: Harvard T.H. Chan School of Public Health
Jian Ouyang: Massachusetts General Hospital Cancer Center
Johannes Kreuzer: Massachusetts General Hospital Cancer Center
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
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
Jessica J. Lin: Massachusetts General Hospital Cancer Center
Wilhelm Haas: Massachusetts General Hospital Cancer Center
Kristopher Sarosiek: Harvard T.H. Chan School of Public Health
Paul E. Hughes: Amgen Inc.
Aaron N. Hata: Massachusetts General Hospital Cancer Center

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58753-y

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