Targeting PGM3 as a Novel Therapeutic Strategy in KRAS/LKB1 Co-Mutant Lung Cancer
Hyunmin Lee1, Feng Cai2, Neil Kelekar1
1Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA.
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.
Insights
Targeting the hexosamine biosynthesis pathway enzyme PGM3 shows promise for treating aggressive non-small-cell lung cancer (NSCLC) with KRAS/STK11 co-mutations. This metabolic vulnerability could lead to new therapeutic strategies for this challenging cancer subtype.
Area of Science:
- Oncology
- Cancer Metabolism
- Biochemistry
Background:
- Concurrent KRAS and STK11 (LKB1) mutations in NSCLC lead to aggressive disease and poor immunotherapy response.
- Previous work identified a dependency on GFPT2 in the hexosamine biosynthesis pathway (HBP) for KRAS/LKB1 co-mutant tumors.
Purpose of the Study:
- To investigate further metabolic vulnerabilities in KRAS/LKB1 co-mutant NSCLC.
- To explore the role of PGM3, downstream of GFPT2 in the HBP, as a potential therapeutic target.
Main Methods:
- Cellular and in vivo models of KRAS/LKB1 co-mutant NSCLC.
- Genetic and pharmacologic inhibition of PGM3.
- Assessment of tumor growth and cellular survival.
Main Results:
- KRAS/LKB1 co-mutant cells exhibit increased dependence on PGM3.
- Suppression of PGM3 significantly reduced tumor growth in vitro and in vivo.
- PGM3 inhibition represents a metabolic vulnerability in this NSCLC subtype.
Conclusions:
- PGM3 is a critical enzyme in the HBP for KRAS/LKB1 co-mutant NSCLC survival.
- Targeting PGM3 offers a novel therapeutic strategy for aggressive NSCLC with these specific mutations.
