Cardiac glycosides display selective efficacy for STK11 mutant lung cancer

Nayoung Kim, Hwa Young Yim, Ningning He, Cheol Jung Lee, Ju Hyun Kim, Jin Sung Choi, Hye Suk Lee, Somin Kim, Euna Jeong, Mee Song, Sang Min Jeon, Woo Young Kim, Gordon Mills, Yong Yeon Cho, Sukjoon Yoon

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Article number29721
JournalScientific Reports
Volume6
DOIs
StatePublished - Jul 19 2016
Externally publishedYes

Fingerprint

Cardiac Glycosides
Lung Neoplasms
Mutation
Digoxin
Heterografts
Digitoxin
AMP-Activated Protein Kinases
Ouabain
Biomarkers
Cell Line
Therapeutics
Growth

ASJC Scopus subject areas

  • General

Cite this

Kim, N., Yim, H. Y., He, N., Lee, C. J., Kim, J. H., Choi, J. S., ... Yoon, S. (2016). Cardiac glycosides display selective efficacy for STK11 mutant lung cancer. Scientific Reports, 6, [29721]. https://doi.org/10.1038/srep29721

Cardiac glycosides display selective efficacy for STK11 mutant lung cancer. / Kim, Nayoung; Yim, Hwa Young; He, Ningning; Lee, Cheol Jung; Kim, Ju Hyun; Choi, Jin Sung; Lee, Hye Suk; Kim, Somin; Jeong, Euna; Song, Mee; Jeon, Sang Min; Kim, Woo Young; Mills, Gordon; Cho, Yong Yeon; Yoon, Sukjoon.

In: Scientific Reports, Vol. 6, 29721, 19.07.2016.

Research output: Contribution to journalArticle

Kim, N, Yim, HY, He, N, Lee, CJ, Kim, JH, Choi, JS, Lee, HS, Kim, S, Jeong, E, Song, M, Jeon, SM, Kim, WY, Mills, G, Cho, YY & Yoon, S 2016, 'Cardiac glycosides display selective efficacy for STK11 mutant lung cancer', Scientific Reports, vol. 6, 29721. https://doi.org/10.1038/srep29721
Kim, Nayoung ; Yim, Hwa Young ; He, Ningning ; Lee, Cheol Jung ; Kim, Ju Hyun ; Choi, Jin Sung ; Lee, Hye Suk ; Kim, Somin ; Jeong, Euna ; Song, Mee ; Jeon, Sang Min ; Kim, Woo Young ; Mills, Gordon ; Cho, Yong Yeon ; Yoon, Sukjoon. / Cardiac glycosides display selective efficacy for STK11 mutant lung cancer. In: Scientific Reports. 2016 ; Vol. 6.
@article{77cfec7d399b4077b2b37027dbcfbf7f,
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.",
author = "Nayoung Kim and Yim, {Hwa Young} and Ningning He and Lee, {Cheol Jung} and Kim, {Ju Hyun} and Choi, {Jin Sung} and Lee, {Hye Suk} and Somin Kim and Euna Jeong and Mee Song and Jeon, {Sang Min} and Kim, {Woo Young} and Gordon Mills and Cho, {Yong Yeon} and Sukjoon Yoon",
year = "2016",
month = "7",
day = "19",
doi = "10.1038/srep29721",
language = "English (US)",
volume = "6",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Cardiac glycosides display selective efficacy for STK11 mutant lung cancer

AU - Kim, Nayoung

AU - Yim, Hwa Young

AU - He, Ningning

AU - Lee, Cheol Jung

AU - Kim, Ju Hyun

AU - Choi, Jin Sung

AU - Lee, Hye Suk

AU - Kim, Somin

AU - Jeong, Euna

AU - Song, Mee

AU - Jeon, Sang Min

AU - Kim, Woo Young

AU - Mills, Gordon

AU - Cho, Yong Yeon

AU - Yoon, Sukjoon

PY - 2016/7/19

Y1 - 2016/7/19

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84979234482&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84979234482&partnerID=8YFLogxK

U2 - 10.1038/srep29721

DO - 10.1038/srep29721

M3 - Article

VL - 6

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 29721

ER -