{"doi":"10.1101/2022.09.29.510137","title":"LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of <i>KRAS</i> -mutant lung cancers","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 inactivating mutations in the tumor suppressor STK11/ LKB1 4 that facilitate tumorigenesis by modulating energy balance 5, 6 , enhancing metastatic potential 7,8 and enabling immune evasion 9,10 . However, whether LKB1 plays a role in modulating cellular responses to therapeutic stress is largely unknown. Here we show that LKB1 suppresses JNK-dependent stress signaling in KRAS -mutant lung cancer cells upon acute loss of oncogenic signaling. In LKB1-deficient KRAS -mutant 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 a previously unknown role for LKB1 in regulating stress signaling and the mitochondrial apoptotic response of cancer cells independent of its tumor suppressor activity mediated by AMPK 11–13 and SIK 14,15 kinases. Additionally, our study reveals a therapy-induced vulnerability in LKB1-deficient KRAS- mutant lung cancer cells that could be exploited as a genotype-informed strategy to improve the efficacy of KRAS-targeted therapies.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":304448,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9548,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":615856,"name":"Mohammed U. 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