LKB1 loss rewires JNK-induced apoptotic protein dynamics through NUAKs and sensitizes KRAS-mutant NSCLC to combined KRASG12C + MCL-1 blockade
Research Square (Research Square)(2022)
Abstract
Abstract The efficacy of molecularly targeted anti-cancer therapies may be limited by the presence of co-occurring mutations within a tumor.1-3 Conversely, these alterations may confer collateral vulnerabilities that can be leveraged for the development of novel therapeutic approaches. KRAS mutant lung cancers are distinguished by recurrent mutations in tumor suppressor genes such as TP53 and STK11/LKB1.4 However, clinically actionable targets associated with these alterations are largely undefined. BH3 mimetics targeting distinct pro-survival BCL-2 family proteins have been proposed to enhance the efficacy of targeted therapies, but no biomarkers exist that can predict which patients are most likely to respond. Here we show that inhibition of oncogenic signaling in KRAS-LKB1 mutant lung cancer cells creates a specific dependency on the anti-apoptotic protein MCL-1 for survival. We find that loss of the LKB1-NUAK signaling axis derepresses a JNK-mediated stress response to KRAS or MEK inhibition, allowing inhibitory phosphorylation of BCL-XL that alters BH3-protein interactions and makes cells vulnerable to concurrent MCL-1 inhibition. These results uncover a previously unknown role for LKB1 in regulating the mitochondrial apoptotic response of cancer cells independent of its tumor suppressor activity mediated by AMPK5-7 and SIK8,9 kinases and suggest a fundamental role for LKB1-NUAKs in suppressing the cellular stress response. Additionally, our study reveals a therapeutically targetable vulnerability in KRAS-LKB1 lung cancer cells and suggests a genotype-informed strategy for improving the efficacy of KRAS-targeted therapies.
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Key words
apoptotic protein dynamics,krasg12c,jnk-induced,kras-mutant
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