title: Cardiac glycosides display selective efficacy for STK11 mutant lung cancer.
abstract: Although STK11 (LKB1) mutation is a major mediator of lung cancer progression, targeted therapy has not been implemented due to STK11 mutations being loss-of-function. Here, we report that targeting the Na(+)/K(+)-ATPase (ATP1A1) is synthetic lethal with STK11 mutations in lung cancer. The cardiac glycosides (CGs) digoxin, digitoxin and ouabain, which directly inhibit ATP1A1 function, exhibited selective anticancer effects on STK11 mutant lung cancer cell lines. Restoring STK11 function reduced the efficacy of CGs. Clinically relevant doses of digoxin decreased the growth of STK11 mutant xenografts compared to wild type STK11 xenografts. Increased cellular stress was associated with the STK11-specific efficacy of CGs. Inhibiting ROS production attenuated the efficacy of CGs, and STK11-AMPK signaling was important in overcoming the stress induced by CGs. Taken together, these results show that STK11 mutation is a novel biomarker for responsiveness to CGs. Inhibition of ATP1A1 using CGs warrants exploration as a targeted therapy for STK11 mutant lung cancer.
authors.affiliation: Center for Advanced Bioinformatics &Systems Medicine, Sookmyung Women's University, Seoul, Republic of Korea.|Department of Biological Sciences, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Nayoung
authors.initials: N
authors.lastname: Kim
authors.affiliation: Center for Advanced Bioinformatics &Systems Medicine, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Hwa Young
authors.initials: HY
authors.lastname: Yim
authors.affiliation: Department of Biological Sciences, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Ningning
authors.initials: N
authors.lastname: He
authors.affiliation: College of Pharmacy, The Catholic University of Korea, Gyeonggi-do, Republic of Korea.
authors.forename: Cheol-Jung
authors.initials: CJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy, The Catholic University of Korea, Gyeonggi-do, Republic of Korea.
authors.forename: Ju Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, The Catholic University of Korea, Gyeonggi-do, Republic of Korea.
authors.forename: Jin-Sung
authors.initials: JS
authors.lastname: Choi
authors.affiliation: College of Pharmacy, The Catholic University of Korea, Gyeonggi-do, Republic of Korea.
authors.forename: Hye Suk
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Center for Advanced Bioinformatics &Systems Medicine, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Somin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Center for Advanced Bioinformatics &Systems Medicine, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Euna
authors.initials: E
authors.lastname: Jeong
authors.affiliation: Center for Advanced Bioinformatics &Systems Medicine, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Mee
authors.initials: M
authors.lastname: Song
authors.affiliation: College of Pharmacy, Ajou University, Gyeonggi-do, Republic of Korea.
authors.forename: Sang-Min
authors.initials: SM
authors.lastname: Jeon
authors.affiliation: RCCFC, College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Woo-Young
authors.initials: WY
authors.lastname: Kim
authors.affiliation: Systems Biology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: College of Pharmacy, The Catholic University of Korea, Gyeonggi-do, Republic of Korea.
authors.forename: Yong-Yeon
authors.initials: YY
authors.lastname: Cho
authors.affiliation: Center for Advanced Bioinformatics &Systems Medicine, Sookmyung Women's University, Seoul, Republic of Korea.|Department of Biological Sciences, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Sukjoon
authors.initials: S
authors.lastname: Yoon
mesh_terms: D000072283:A549 Cells; D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D002301:Cardiac Glycosides / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004074:Digitoxin / Q000494:pharmacology; D004077:Digoxin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008819:Mice, Nude; D009154:Mutation; D010042:Ouabain / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D023041:Xenograft Model Antitumor Assays
chemical_list: D002301:Cardiac Glycosides; D002316:Cardiotonic Agents; D010042:Ouabain; D004077:Digoxin; D004074:Digitoxin; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases