2. Academic Validation
  3. Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer

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

  • Nat Metab. 2024 Jun 14. doi: 10.1038/s42255-024-01066-z.
Hyun Min Lee 1,  Nefertiti Muhammad 2,  Elizabeth L Lieu 2,  Feng Cai 3,  Jiawei Mu 4,  Yun-Sok Ha 5,  Guoshen Cao 6,  Chamey Suchors 7,  Kenneth Joves 2,  Constantinos Chronis 2,  Kailong Li 4,  Gregory S Ducker 6,  Kellen Olszewski 8,  Ling Cai 9,  Derek B Allison 10,  Sara E Bachert 10,  William R Ewing 8,  Harvey Wong 11,  Hyosun Seo 2,  Isaac Y Kim 1,  Brandon Faubert 12,  James Kim 7,  Jiyeon Kim 13 14
Affiliations

Affiliations

  • 1 Department of Urology, Yale School of Medicine, New Haven, CT, USA.
  • 2 Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
  • 3 Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, TX, USA.
  • 4 Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 5 Department of Urology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea.
  • 6 Department of Biochemistry, University of Utah, Salt Lake City, UT, USA.
  • 7 Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA.
  • 8 Barer Institute, Philadelphia, PA, USA.
  • 9 Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, TX, USA.
  • 10 Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY, USA.
  • 11 Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
  • 12 Department of Medicine-Hematology and Oncology, University of Chicago, Chicago, IL, USA.
  • 13 Department of Urology, Yale School of Medicine, New Haven, CT, USA. jiyeon.kim1@yale.edu.
  • 14 Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, USA. jiyeon.kim1@yale.edu.
PMID: 38877143 DOI: 10.1038/s42255-024-01066-z
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.

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