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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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58753-y |
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| author | 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 |
| author_facet | 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 |
| author_sort | Chendi Li |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-9af98f76209242558ca0d8f9f9c84ef6 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-9af98f76209242558ca0d8f9f9c84ef62025-08-20T01:47:32ZengNature PortfolioNature Communications2041-17232025-05-0116111610.1038/s41467-025-58753-yLKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancersChendi Li0Mohammed Usman Syed1Anahita Nimbalkar2Yi Shen3Melissa D. Vieira4Cameron Fraser5Zintis Inde6Xingping Qin7Jian Ouyang8Johannes Kreuzer9Sarah E. Clark10Grace Kelley11Emily M. Hensley12Robert Morris13Raul Lazaro14Brian Belmonte15Audris Oh16Makeba Walcott17Christopher S. Nabel18Sean Caenepeel19Anne Y. Saiki20Karen Rex21J. Russell Lipford22Rebecca S. Heist23Jessica J. Lin24Wilhelm Haas25Kristopher Sarosiek26Paul E. Hughes27Aaron N. Hata28Massachusetts General Hospital Cancer CenterMassachusetts General Hospital Cancer CenterMassachusetts General Hospital Cancer CenterMassachusetts General Hospital Cancer CenterMassachusetts General Hospital Cancer CenterJohn B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public HealthJohn B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public HealthJohn B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public HealthMassachusetts General Hospital Cancer CenterMassachusetts General Hospital Cancer CenterMassachusetts General Hospital Cancer CenterMassachusetts General Hospital Cancer CenterMassachusetts General Hospital Cancer CenterMassachusetts General Hospital Cancer CenterAmgen Research, Amgen Inc.Amgen Research, Amgen Inc.Massachusetts General Hospital Cancer CenterMassachusetts General Hospital Cancer CenterMassachusetts General Hospital Cancer CenterAmgen Research, Amgen Inc.Amgen Research, Amgen Inc.Amgen Research, Amgen Inc.Amgen Research, Amgen Inc.Massachusetts General Hospital Cancer CenterMassachusetts General Hospital Cancer CenterMassachusetts General Hospital Cancer CenterJohn B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public HealthAmgen Research, Amgen Inc.Massachusetts General Hospital Cancer CenterAbstract 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.https://doi.org/10.1038/s41467-025-58753-y |
| spellingShingle | 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 LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers Nature Communications |
| title | LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers |
| title_full | LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers |
| title_fullStr | LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers |
| title_full_unstemmed | LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers |
| title_short | LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers |
| title_sort | lkb1 regulates jnk dependent stress signaling and apoptotic dependency of kras mutant lung cancers |
| url | https://doi.org/10.1038/s41467-025-58753-y |
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