LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers
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.
Authors
- Robert Morris (ORCID: https://orcid.org/0000-0003-1615-5915)
- Wilhelm Haas (ORCID: https://orcid.org/0000-0001-8225-9099)
- Sarah Elizabeth Clark (ORCID: https://orcid.org/0000-0002-5975-5032)
- Audris Oh
- Helena L.A. Vieira (ORCID: https://orcid.org/0000-0001-9415-3742)
- Johannes Kreuzer (ORCID: https://orcid.org/0000-0003-4716-2843)
- Xingping Qin (ORCID: https://orcid.org/0000-0003-3263-0843)
- Kristopher A. Sarosiek (ORCID: https://orcid.org/0000-0002-4618-5085)
- Chendi Li (ORCID: https://orcid.org/0009-0000-2610-042X)
- Anahita Nimbalkar
- Christopher S. Nabel (ORCID: https://orcid.org/0000-0001-6515-8579)
- Zintis Inde (ORCID: https://orcid.org/0000-0001-5564-1698)
- Anne Y. Saiki (ORCID: https://orcid.org/0000-0003-3913-1860)
- Jian Ouyang (ORCID: https://orcid.org/0000-0001-5773-6850)
- Rebecca S. Heist (ORCID: https://orcid.org/0000-0002-7397-2009)
- Beatrice Belmonte (ORCID: https://orcid.org/0000-0001-9668-0925)
- Makeba Walcott
- Mohammed U. Syed (ORCID: https://orcid.org/0000-0002-6207-1694)
- W. Marston Linehan (ORCID: https://orcid.org/0000-0001-7373-3916)
- Aaron N. Hata (ORCID: https://orcid.org/0000-0002-6127-318X)
- Cameron Fraser (ORCID: https://orcid.org/0000-0002-8180-5913)
- Yi Shen (ORCID: https://orcid.org/0000-0003-3978-6285)
- Paul E. Hughes (ORCID: https://orcid.org/0000-0003-1095-9883)
- Emily Hensley
- Sean Caenepeel
- Karen Rex
- J. Russell Lipford
- Grace Kelley
- Raul Lazaro
Institutions
- Amgen (United States) (US)
- Harvard University (US)
- Medical University of South Carolina (US)
- Massachusetts General Hospital (US)
- MUSC Hollings Cancer Center (US)
- Center for Cancer Research (US)
- Center for Systems Biology (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-02
- DOI
- https://doi.org/10.1038/s41467-025-58753-y
- Citations
- 6
- Primary Topic
- Cell death mechanisms and regulation
- Type
- article
- Field-Weighted Citation Impact
- 4.84