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이현민Hyun Min Lee

Yale School of Medicine

Nat Metab., Jun 14 2024, | https://doi.org/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 ¹, Nefertiti Muhammad², Elizabeth L. Lieu², Feng Cai³, Jiawei Mu⁴, Yun-Sok Ha⁵, Guoshen Cao⁶, Chamey Suchors⁷, Kenneth Joves², Constantinos Chronis², Kailong Li ⁴, Gregory S. Ducker⁶, Kellen Olszewski⁸, Ling Cai⁹, Derek B. Allison¹⁰, Sara E. Bachert¹⁰, William R. Ewing⁸, Harvey Wong¹¹, Hyosun Seo², Isaac Y. Kim¹, Brandon Faubert¹², James Kim⁷ & Jiyeon Kim^1,13

¹Department of Urology, Yale School of Medicine, New Haven, CT, USA.

²Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.

³Children’s Medical Center Research Institute, UT Southwestern Medical Center, Dallas, TX, USA.

⁴Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.

⁵Department of Urology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea.

⁶Department of Biochemistry, University of Utah, Salt Lake City, UT, USA.

⁷Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA.

⁸Barer Institute, Philadelphia, PA, USA.

⁹Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, TX, USA.

¹⁰Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY, USA.

¹¹Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.

¹²Department of Medicine-Hematology and Oncology, University of Chicago, Chicago, IL, USA.

¹³Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, USA

Corresponding author

Correspondence to Jiyeon Kim.

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.

논문정보

형식Research article
게재일2024년 06월 (BRIC 등록일 2024-06-18)
연구진국내+국외 연구진
분야 생명과학 > 세포생물학

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