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Cardiac glycosides display selective efficacy for STK11 mutant lung cancer
Nayoung Kim1,2, Hwa Young Yim1, Ningning He2
1Center for Advanced Bioinformatics &Systems Medicine, Sookmyung Women's University, Seoul, Republic of Korea.
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.
Insights
STK11 mutations in lung cancer can be targeted using cardiac glycosides (CGs) that inhibit Na(+)/K(+)-ATPase (ATP1A1). This synthetic lethality offers a new therapeutic strategy for STK11-mutant lung cancers.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- STK11 (LKB1) mutations drive lung cancer progression but lack targeted therapies due to their loss-of-function nature.
- Identifying vulnerabilities in STK11-mutant lung cancer is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the potential of targeting Na(+)/K(+)-ATPase (ATP1A1) as a synthetic lethal strategy for STK11-mutant lung cancer.
- To evaluate the efficacy of cardiac glycosides (CGs) as inhibitors of ATP1A1 in STK11-mutant lung cancer models.
Main Methods:
- Screening of STK11-mutant and wild-type lung cancer cell lines for sensitivity to CGs (digoxin, digitoxin, ouabain).
- Assessment of CG efficacy in STK11-mutant xenograft models.
- Analysis of cellular stress, reactive oxygen species (ROS) production, and STK11-AMPK signaling pathways.
Main Results:
- Cardiac glycosides (CGs) demonstrated selective anticancer effects against STK11-mutant lung cancer cell lines.
- Digoxin treatment significantly reduced tumor growth in STK11-mutant xenografts compared to wild-type.
- CG efficacy was linked to increased cellular stress, ROS production, and relied on STK11-AMPK signaling.
Conclusions:
- STK11 mutation is identified as a predictive biomarker for response to CGs in lung cancer.
- Targeting ATP1A1 with CGs represents a promising, novel therapeutic approach for STK11-mutant lung cancer.
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