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

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

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 suppre...

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Main Authors: 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, Aaron N. Hata
Format: Article
Language:English
Published: Nature Portfolio 2025-05-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-58753-y
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Summary: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.
ISSN:2041-1723

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