Targeting PGM3 as a Novel Therapeutic Strategy in Co-Mutant Lung Cancer.

In non-small-cell lung cancer (NSCLC), concurrent mutations in the oncogene and tumor suppressor (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 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 co-mutants. Here, we found that co-mutant cells also exhibit an increased dependence on -acetylglucosamine-phosphate mutase 3 (PGM3), an enzyme downstream of GFPT2. Genetic or pharmacologic suppression of PGM3 reduced co-mutant tumor growth in both in vitro and in vivo settings. Our results define an additional metabolic vulnerability in co-mutant tumors to the HBP and provide a rationale for targeting PGM3 in this aggressive subtype of NSCLC.