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

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.

Canonical Hedgehog Pathway and Noncanonical GLI Transcription Factor Activation in Cancer.

The Hedgehog signaling pathway is one of the fundamental pathways required for development and regulation of postnatal regeneration in a variety of tissues. The pathway has also been associated with cancers since the identification of a mutation in one of its components, PTCH, as the cause of Basal Cell Nevus Syndrome, which is associated with several cancers. Our understanding of the pathway in tumorigenesis has expanded greatly since that initial discovery over two decades ago. The pathway has tumor-suppressive and oncogenic functions depending on the context of the cancer. Furthermore, noncanonical activation of GLI transcription factors has been reported in a number of tumor types. Here, we review the roles of canonical Hedgehog signaling pathway and noncanonical GLI activation in cancers, particularly epithelial cancers, and discuss an emerging concept of the distinct outcomes that these modes have on cancer initiation and progression.