Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer

Hyun Min Lee; Nefertiti Muhammad; Elizabeth L. Lieu; Feng Cai; Jiawei Mu; Yun Sok Ha; Guoshen Cao; Chamey Suchors; Kenneth Joves; Constantinos Chronis; Kailong Li; Gregory S. Ducker; Kellen Olszewski; Ling Cai; Derek B. Allison; Sara E. Bachert; William R. Ewing; Harvey Wong; Hyosun Seo; Isaac Y. Kim; Brandon Faubert; James Kim; Jiyeon Kim

doi:10.1038/s42255-024-01066-z

Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer

Hyun Min Lee, Nefertiti Muhammad, Elizabeth L. Lieu, Feng Cai, Jiawei Mu, Yun Sok Ha, Guoshen Cao, Chamey Suchors, Kenneth Joves, Constantinos Chronis, Kailong Li, Gregory S. Ducker, Kellen Olszewski, Ling Cai, Derek B. Allison, Sara E. Bachert, William R. Ewing, Harvey Wong, Hyosun Seo, Isaac Y. KimBrandon Faubert, James Kim, Jiyeon Kim

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

Non-small-cell lung cancer (NSCLC) with concurrent mutations in KRAS and the tumour suppressor LKB1 (KL NSCLC) is refractory to most therapies and has one of the worst predicted outcomes. Here we describe a KL-induced metabolic vulnerability associated with serine–glycine-one-carbon (SGOC) metabolism. Using RNA-seq and metabolomics data from human NSCLC, we uncovered that LKB1 loss enhanced SGOC metabolism via serine hydroxymethyltransferase (SHMT). LKB1 loss, in collaboration with KEAP1 loss, activated SHMT through inactivation of the salt-induced kinase (SIK)–NRF2 axis and satisfied the increased demand for one-carbon units necessary for antioxidant defence. Chemical and genetic SHMT suppression increased cellular sensitivity to oxidative stress and cell death. Further, the SHMT inhibitor enhanced the in vivo therapeutic efficacy of paclitaxel (first-line NSCLC therapy inducing oxidative stress) in KEAP1-mutant KL tumours. The data reveal how this highly aggressive molecular subtype of NSCLC fulfills their metabolic requirements and provides insight into therapeutic strategies.

Original language	English (US)
Pages (from-to)	1310-1328
Number of pages	19
Journal	Nature Metabolism
Volume	6
Issue number	7
DOIs	https://doi.org/10.1038/s42255-024-01066-z
State	Published - Jul 2024
Externally published	Yes

All Science Journal Classification (ASJC) codes

Internal Medicine
Endocrinology, Diabetes and Metabolism
Physiology (medical)
Cell Biology

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Lee, H. M., Muhammad, N., Lieu, E. L., Cai, F., Mu, J., Ha, Y. S., Cao, G., Suchors, C., Joves, K., Chronis, C., Li, K., Ducker, G. S., Olszewski, K., Cai, L., Allison, D. B., Bachert, S. E., Ewing, W. R., Wong, H., Seo, H., ... Kim, J. (2024). Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer. Nature Metabolism, 6(7), 1310-1328. https://doi.org/10.1038/s42255-024-01066-z

@article{22d443d733eb40a8851802bf38228990,

title = "Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer",

abstract = "Non-small-cell lung cancer (NSCLC) with concurrent mutations in KRAS and the tumour suppressor LKB1 (KL NSCLC) is refractory to most therapies and has one of the worst predicted outcomes. Here we describe a KL-induced metabolic vulnerability associated with serine–glycine-one-carbon (SGOC) metabolism. Using RNA-seq and metabolomics data from human NSCLC, we uncovered that LKB1 loss enhanced SGOC metabolism via serine hydroxymethyltransferase (SHMT). LKB1 loss, in collaboration with KEAP1 loss, activated SHMT through inactivation of the salt-induced kinase (SIK)–NRF2 axis and satisfied the increased demand for one-carbon units necessary for antioxidant defence. Chemical and genetic SHMT suppression increased cellular sensitivity to oxidative stress and cell death. Further, the SHMT inhibitor enhanced the in vivo therapeutic efficacy of paclitaxel (first-line NSCLC therapy inducing oxidative stress) in KEAP1-mutant KL tumours. The data reveal how this highly aggressive molecular subtype of NSCLC fulfills their metabolic requirements and provides insight into therapeutic strategies.",

author = "Lee, {Hyun Min} and Nefertiti Muhammad and Lieu, {Elizabeth L.} and Feng Cai and Jiawei Mu and Ha, {Yun Sok} and Guoshen Cao and Chamey Suchors and Kenneth Joves and Constantinos Chronis and Kailong Li and Ducker, {Gregory S.} and Kellen Olszewski and Ling Cai and Allison, {Derek B.} and Bachert, {Sara E.} and Ewing, {William R.} and Harvey Wong and Hyosun Seo and Kim, {Isaac Y.} and Brandon Faubert and James Kim and Jiyeon Kim",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature Limited 2024. corrected publication 2024.",

year = "2024",

month = jul,

doi = "10.1038/s42255-024-01066-z",

language = "English (US)",

volume = "6",

pages = "1310--1328",

journal = "Nature Metabolism",

issn = "2522-5812",

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Lee, HM, Muhammad, N, Lieu, EL, Cai, F, Mu, J, Ha, YS, Cao, G, Suchors, C, Joves, K, Chronis, C, Li, K, Ducker, GS, Olszewski, K, Cai, L, Allison, DB, Bachert, SE, Ewing, WR, Wong, H, Seo, H, Kim, IY, Faubert, B, Kim, J & Kim, J 2024, 'Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer', Nature Metabolism, vol. 6, no. 7, pp. 1310-1328. https://doi.org/10.1038/s42255-024-01066-z

TY - JOUR

T1 - Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer

AU - Lee, Hyun Min

AU - Muhammad, Nefertiti

AU - Lieu, Elizabeth L.

AU - Cai, Feng

AU - Mu, Jiawei

AU - Ha, Yun Sok

AU - Cao, Guoshen

AU - Suchors, Chamey

AU - Joves, Kenneth

AU - Chronis, Constantinos

AU - Li, Kailong

AU - Ducker, Gregory S.

AU - Olszewski, Kellen

AU - Cai, Ling

AU - Allison, Derek B.

AU - Bachert, Sara E.

AU - Ewing, William R.

AU - Wong, Harvey

AU - Seo, Hyosun

AU - Kim, Isaac Y.

AU - Faubert, Brandon

AU - Kim, James

AU - Kim, Jiyeon

N1 - Publisher Copyright: © The Author(s), under exclusive licence to Springer Nature Limited 2024. corrected publication 2024.

PY - 2024/7

Y1 - 2024/7

N2 - Non-small-cell lung cancer (NSCLC) with concurrent mutations in KRAS and the tumour suppressor LKB1 (KL NSCLC) is refractory to most therapies and has one of the worst predicted outcomes. Here we describe a KL-induced metabolic vulnerability associated with serine–glycine-one-carbon (SGOC) metabolism. Using RNA-seq and metabolomics data from human NSCLC, we uncovered that LKB1 loss enhanced SGOC metabolism via serine hydroxymethyltransferase (SHMT). LKB1 loss, in collaboration with KEAP1 loss, activated SHMT through inactivation of the salt-induced kinase (SIK)–NRF2 axis and satisfied the increased demand for one-carbon units necessary for antioxidant defence. Chemical and genetic SHMT suppression increased cellular sensitivity to oxidative stress and cell death. Further, the SHMT inhibitor enhanced the in vivo therapeutic efficacy of paclitaxel (first-line NSCLC therapy inducing oxidative stress) in KEAP1-mutant KL tumours. The data reveal how this highly aggressive molecular subtype of NSCLC fulfills their metabolic requirements and provides insight into therapeutic strategies.

AB - Non-small-cell lung cancer (NSCLC) with concurrent mutations in KRAS and the tumour suppressor LKB1 (KL NSCLC) is refractory to most therapies and has one of the worst predicted outcomes. Here we describe a KL-induced metabolic vulnerability associated with serine–glycine-one-carbon (SGOC) metabolism. Using RNA-seq and metabolomics data from human NSCLC, we uncovered that LKB1 loss enhanced SGOC metabolism via serine hydroxymethyltransferase (SHMT). LKB1 loss, in collaboration with KEAP1 loss, activated SHMT through inactivation of the salt-induced kinase (SIK)–NRF2 axis and satisfied the increased demand for one-carbon units necessary for antioxidant defence. Chemical and genetic SHMT suppression increased cellular sensitivity to oxidative stress and cell death. Further, the SHMT inhibitor enhanced the in vivo therapeutic efficacy of paclitaxel (first-line NSCLC therapy inducing oxidative stress) in KEAP1-mutant KL tumours. The data reveal how this highly aggressive molecular subtype of NSCLC fulfills their metabolic requirements and provides insight into therapeutic strategies.

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U2 - 10.1038/s42255-024-01066-z

DO - 10.1038/s42255-024-01066-z

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AN - SCOPUS:85195975895

SN - 2522-5812

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JO - Nature Metabolism

JF - Nature Metabolism

IS - 7

ER -

Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer

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