Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer.
Hyun Min LeeNefertiti MuhammadElizabeth L LieuFeng CaiJiawei MuYun-Sok HaGuoshen CaoChamey SuchorsKenneth JovesConstantinos ChronisKailong LiGregory S DuckerKellen OlszewskiLing CaiDerek B AllisonSara E BachertWilliam R EwingHarvey WongHyosun SeoIsaac Y KimBrandon FaubertJames KimJiyeon KimPublished in: Nature metabolism (2024)
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.
Keyphrases
- oxidative stress
- small cell lung cancer
- diabetic rats
- advanced non small cell lung cancer
- rna seq
- single cell
- cell death
- wild type
- brain metastases
- dna damage
- ischemia reperfusion injury
- protein kinase
- electronic health record
- induced apoptosis
- endothelial cells
- climate change
- drug induced
- gene expression
- stem cells
- anti inflammatory
- squamous cell carcinoma
- type diabetes
- epidermal growth factor receptor
- small molecule
- radiation therapy
- data analysis
- cell proliferation
- mass spectrometry
- mesenchymal stem cells
- bone marrow
- pluripotent stem cells
- copy number