LKB1 loss rewires JNK-induced apoptotic protein dynamics through NUAKs and sensitizes KRAS-mutant NSCLC to combined KRASG12C + MCL-1 blockade

The recently approved KRASG12C inhibitor sotorasib induces durable responses of KRASG12C -mutant non-small cell lung cancers (NSCLCs), however, some patients do not derive benefit. Identification of specific vulnerabilities conferred by co-occurring mutations may enable the development of biomarker-driven combination therapies in distinct subsets of patients. We report that co-occurring loss of STK11 /LKB1 is associated with a drug-induced vulnerability of KRAS -mutant NSCLCs to MCL-1 inhibition. In LKB1-deficient cells, inhibition of KRAS-MAPK signaling leads to hyperactivated JNK, which phosphorylates BCL-XL and impairs its ability to sequester BIM, thus creating a dependency on MCL-1 for survival. In LKB1-proficient cells, LKB1 suppresses drug-induced JNK hyperactivation in a NUAK-dependent manner. Ex vivo treatment of tumors from LKB1-deficient but not LKB1 wild-type KRAS -mutant NSCLC patients with sotorasib or trametinib increased MCL-1 dependence. These results uncover a novel role for the LKB1-NUAK axis in regulation of apoptotic dependency and suggest a genotype-directed therapeutic approach for KRAS-LKB1 mutant NSCLC. ### Competing Interest Statement A.N.H. has received research support from Amgen, Eli Lilly, Pfizer, BridgeBio, Nuvalent Inc., Roche/Genentech, Blueprint Medicines, Scorpion Therapeutics, Bristol-Myers Squibb, C4 Therapeutics, Novartis and Relay Therapeutics; has served as a compensated consultant for Nuvalent, Tolremo Therapeutics, Engine Biosciences and TigaTx. RSH has served as a compensated consultant for Abbvie, Daichii Sankyo, EMD Serono, Novartis, Regeneron. Research funding to institution, not to self: Abbvie, Agios, Corvus, Exelixis, Genentech, Lilly, Mirati, Novartis, Turning Point. J.J.L. reports consulting fees from Genentech, C4 Therapeutics, Blueprint Medicines, Nuvalent, Bayer, Elevation Oncology, Novartis, Mirati Therapeutics, and Turning Point Therapeutics; honorarium and travel support from Pfizer; institutional research funding from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche, Linnaeus Therapeutics, Nuvalent, and Novartis; and CME funding from OncLive, MedStar Health, and Northwell Health. C.S.N. owns equity (stock) in Opko Therapeutics and has received royalty income from ThermoFisher (previously Life Sciences). S.C., A.Y.S., K.R., J.R.L., P.E.H are employees of and have ownership (including stock, patents, etc.) interest in Amgen. The remaining authors declare no competing interests.