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.
Subject(s)
AMP-Activated Protein Kinase Kinases , Antioxidants , Carcinoma, Non-Small-Cell Lung , Glycine Hydroxymethyltransferase , Kelch-Like ECH-Associated Protein 1 , Lung Neoplasms , Mutation , Protein Serine-Threonine Kinases , Proto-Oncogene Proteins p21(ras) , Kelch-Like ECH-Associated Protein 1/metabolism , Kelch-Like ECH-Associated Protein 1/genetics , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Glycine Hydroxymethyltransferase/genetics , Glycine Hydroxymethyltransferase/metabolism , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Antioxidants/metabolism , Animals , Oxidative Stress , Mice , Cell Line, Tumor , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/geneticsABSTRACT
Recent advances in our understanding of host immune and cancer cells interactions have made immunotherapy a prominent choice in cancer treatment. Despite such promise, cell-based immunotherapies remain inapplicable to many patients due to severe limitations in the availability and quality of immune cells isolated from donors. Reprogramming technologies that facilitate the engineering of cell types of interest, are emerging as a putative solution to such challenges. Here we focus on the recent progress being made in reprogramming technologies with respect to the immune system and their potential for clinical applications.