In vivo metabolomics identifies CD38 as an emergent vulnerability in LKB1-mutant lung cancer

LKB1/STK11 is a serine/threonine kinase that plays a major role in controlling cell metabolism, resulting in potential therapeutic vulnerabilities in LKB1-mutant cancers. Here, we identify the NAD+ degrading ectoenzyme, CD38, as a new target in LKB1-mutant NSCLC. Metabolic profiling of genetically engineered mouse models (GEMMs) revealed that LKB1 mutant lung cancers have a striking increase in ADP-ribose, a breakdown product of the critical redox co-factor, NAD+. Surprisingly, compared with other genetic subsets, murine and human LKB1-mutant NSCLC show marked overexpression of the NAD+-catabolizing ectoenzyme, CD38 on the surface of tumor cells. Loss of LKB1 or inactivation of Salt-Inducible Kinases (SIKs)—key downstream effectors of LKB1— induces CD38 transcription induction via a CREB binding site in the CD38 promoter. Treatment with the FDA-approved anti-CD38 antibody, daratumumab, inhibited growth of LKB1-mutant NSCLC xenografts. Together, these results reveal CD38 as a promising therapeutic target in patients with LKB1 mutant lung cancer. SIGNIFICANCE Loss-of-function mutations in the LKB1 tumor suppressor of lung adenocarcinoma patients and are associated with resistance to current treatments. Our study identified CD38 as a potential therapeutic target that is highly overexpressed in this specific subtype of cancer, associated with a shift in NAD homeostasis. ### Competing Interest Statement K.K.W. is a founder and equity holder of G1 Therapeutics and has sponsored research agreements with Takeda, TargImmune, Bristol-Myers Squibb (BMS), Mirati, Merus, Alkermes, and consulting and sponsored research agreements with AstraZeneca, Janssen, Pfizer, Novartis, Merck, Zentalis, BridgeBio and Blueprint. C.M.R. reports personal fees from AbbVie, Amgen, Ascentage, AstraZeneca, Bicycle, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Jansen, Jazz, Lilly/Loxo, Pfizer, PharmaMar, Syros, Vavotek, Bridge Medicines and Harpoon Therapeutics, outside the submitted work. B.G.N. reports other support from NYU Langone Health, Northern Biologics, and Navire Pharma, personal fees and other support from Lighthorse Therapeutics, Arvinas, Recursion Pharma, GLG Group, and Repare Therapeutics, and grants from the NCI/NIH (R21CA267362, R01CA248896, and P30CA016087) during the conduct of the study; a patent for 63402606 pending; and during the course of performing these experiments, his wife owned personal shares in Amgen and Regeneron. B.G.N. also own shares of Mirati. B.G.N. is the co-founder, hold equity and receive consulting revenue from Aethon Therapeutics. A.N.H. has received research support from Amgen, Blueprint Medicines, BridgeBio, Bristol-Myers Squibb, C4 Therapeutics, Eli Lilly, Nuvalent, Pfizer, Roche/Genentech, Scorpion Therapeutics; has served as a compensated consultant for Nuvalent, Tolremo Therapeutics, Engine Biosciences and TigaTx. S.K. reports grants from Puretech Health and Argenx BVBA, and grants and personal fees from Black Diamond Therapeutics outside the submitted work; a patent for PCT/US2022/018171 pending; and is a cofounder of and holds equity in Revalia Bio.