Li Chendi, Syed Mohammed Usman, Nimbalkar Anahita, Shen Yi, Vieira Melissa D, Fraser Cameron, Inde Zintis, Qin Xingping, Ouyang Jian, Kreuzer Johannes, Clark Sarah E, Kelley Grace, Hensley Emily M, Morris Robert, Lazaro Raul, Belmonte Brian, Oh Audris, Walcott Makeba, Nabel Christopher S, Caenepeel Sean, Saiki Anne Y, Rex Karen, Lipford J Russell, Heist Rebecca S, Lin Jessica J, Haas Wilhelm, Sarosiek Kristopher, Hughes Paul E, Hata Aaron N
Massachusetts General Hospital Cancer Center, Boston, MA, USA.
Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Nat Commun. 2025 May 2;16(1):4112. doi: 10.1038/s41467-025-58753-y.
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.
分子靶向疗法的疗效可能会受到肿瘤内同时发生的突变的限制。相反，这些改变可能会带来可被用于治疗的旁系脆弱性。KRAS突变型肺癌的特征是肿瘤抑制因子STK11/LKB1反复缺失。LKB1是否调节细胞对治疗应激的反应似乎尚不清楚。在这里，我们表明，在LKB1缺陷的KRAS突变型肺癌细胞中，抑制KRAS或其下游效应物MEK会导致JNK过度激活，这是由于NUAK介导的PP1B磷酸酶活性丧失所致。JNK介导的BCL-XL抑制性磷酸化改变了凋亡依赖性，使LKB1缺陷细胞易受MCL-1抑制的影响。这些结果揭示了LKB1在调节应激信号和线粒体凋亡方面的未知作用，这与其由AMPK和SIK介导的肿瘤抑制活性无关。此外，我们的研究揭示了LKB1缺陷的KRAS突变型肺癌中一种治疗诱导的脆弱性，可将其作为一种基于基因型的策略来提高KRAS靶向疗法的疗效。
