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. Kim

Brandon Faubert, James Kim, Jiyeon Kim

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

17 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
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

Bibliographical note

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

Funding

We thank J. D. Rabinowitz (Princeton University) for providing SHIN2, and R. J. DeBerardinis (UTSW), P. M. Wehn (BridgeBio Pharma) and C.-H. Lee (YSM) for feedback. Jiyeon Kim (YSM) is supported by a Career Enhancement Program Grant from the Yale SPORE in Lung Cancer P50CA196530, the NCI 1K22CA226676-01A1, NCI 1R37CA285640-01A1, American Lung Association (IA-828202) and the American Cancer Society (RSG-21-153-01-CCB). C.C. was supported by NIH P01HL160469. G.S.D. was supported by NCI R00CA215307. K.L. is supported by the Fundamental Research Funds for the Central Universities (BMU2021YJ073). James Kim (UTSW) is supported by NCI 1R01CA258684, 1R01CA196851 and P50CA070907. D.B.A. is supported by P30CA177558. B.F. is supported by the NCI R00CA237724.

Funders	Funder number
Fundamental Research Funds for the Central Universities	P30CA177558, 1R01CA258684, 1R01CA196851, BMU2021YJ073, R00CA237724, P50CA070907
National Childhood Cancer Registry – National Cancer Institute	1K22CA226676-01A1, 1R37CA285640-01A1
American Lung Association	IA-828202
National Institutes of Health (NIH)	P01HL160469, R00CA215307
American Cancer Society-Michigan Cancer Research Fund	RSG-21-153-01-CCB

ASJC Scopus subject areas

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s42255-024-01066-z

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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

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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",

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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

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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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JO - Nature Metabolism

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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