Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer.
Nat Metab
; 6(7): 1310-1328, 2024 Jul.
Article
em En
| MEDLINE
| ID: mdl-38877143
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Glicina Hidroximetiltransferase
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Proteínas Proto-Oncogênicas p21(ras)
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Proteínas Serina-Treonina Quinases
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Carcinoma Pulmonar de Células não Pequenas
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Proteína 1 Associada a ECH Semelhante a Kelch
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Quinases Proteína-Quinases Ativadas por AMP
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Neoplasias Pulmonares
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Mutação
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Antioxidantes
Limite:
Animals
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Humans
Idioma:
En
Revista:
Nat Metab
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos