Abstract
In non-small-cell lung cancer (NSCLC), concurrent mutations in the oncogene KRAS and tumor suppressor STK11 (also known as LKB1) confer an aggressive malignant phenotype, an unfavourability towards immunotherapy, and overall poor prognoses in patients. In a previous study, we showed that murine KRAS/LKB1 co-mutant tumors and human co-mutant cancer cells have an enhanced dependence on glutamine-fructose-6-phosphate transaminase 2 (GFPT2), a rate-limiting enzyme in the hexosamine biosynthesis pathway (HBP), which could be targeted to reduce survival of KRAS/LKB1 co-mutants. Here, we found that KRAS/LKB1 co-mutant cells also exhibit an increased dependence on N-acetylglucosamine-phosphate mutase 3 (PGM3), an enzyme downstream of GFPT2. Genetic or pharmacologic suppression of PGM3 reduced KRAS/LKB1 co-mutant tumor growth in both in vitro and in vivo settings. Our results define an additional metabolic vulnerability in KRAS/LKB1 co-mutant tumors to the HBP and provide a rationale for targeting PGM3 in this aggressive subtype of NSCLC.
Highlights
Lung cancer is the leading cause of cancer-related mortality worldwide with a 5-year survival rate of only 21% [1]
non-small-cell lung cancer (NSCLC) with concurrent mutations in the oncogene KRAS and the tumor suppressor LKB1 is refractory to most therapies and has the worst predicted outcomes
We showed that KL co-mutant tumors require glutamine-fructose-6-phosphate transaminase 2 (GFPT2) in the hexosamine biosynthesis pathway (HBP) for their survival and proliferation
Summary
Lung cancer is the leading cause of cancer-related mortality worldwide with a 5-year survival rate of only 21% [1]. Through the implementation of large-scale sequencing efforts, tumor suppressors and oncogenes mutated in NSCLC have been defined. Most of these mutations are not yet subject to targeted therapy. The incidence of concomitant KRAS and LKB1 mutations in NSCLC is estimated to be ~25% of all KRAS-driven NSCLC. While patients with these co-mutations have poor clinical outcomes and a more aggressive malignancy that frequently develops brain metastases [6,7], there are currently no therapies available to cure KRAS/LKB1 (KL) co-mutant NSCLC. There is an unmet need to discover the molecular mechanism by which KL co-mutations alter signal transduction pathways in tumors and determine therapeutic avenues for targeting pathways, without affecting normal tissue physiology
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