The hexosamine biosynthesis pathway is a targetable liability in KRAS/LKB1 mutant lung cancer.

Abstract

In non-small-cell lung cancer (NSCLC), concurrent mutations in the oncogene KRAS and the tumour suppressor STK11 (also known as LKB1) encoding the kinase LKB1 result in aggressive tumours prone to metastasis but with liabilities arising from reprogrammed metabolism. We previously demonstrated perturbed nitrogen metabolism and addiction to an unconventional pathway of pyrimidine synthesis in KRAS/LKB1 co-mutant cancer cells. To gain broader insight into metabolic reprogramming in NSCLC, we analysed tumour metabolomes in a series of genetically engineered mouse models with oncogenic KRAS combined with mutations in LKB1 or p53. Metabolomics and gene expression profiling pointed towards activation of the hexosamine biosynthesis pathway (HBP), another nitrogen-related metabolic pathway, in both mouse and human KRAS/LKB1 co-mutant tumours. KRAS/LKB1 co-mutant cells contain high levels of HBP metabolites, higher flux through the HBP pathway and elevated dependence on the HBP enzyme glutamine-fructose-6-phosphate transaminase [isomerizing] 2 (GFPT2). GFPT2 inhibition selectively reduced KRAS/LKB1 co-mutant tumour cell growth in culture, xenografts and genetically modified mice. Our results define a new metabolic vulnerability in KRAS/LKB1 co-mutant tumours and provide a rationale for targeting GFPT2 in this aggressive NSCLC subtype.

• Authors: Jiyeon Kim, Hyun Min Lee, Feng Cai, Bookyung Ko, Chendong Yang, Elizabeth L Lieu, Nefertiti Muhammad, Shawn Rhyne, Kailong Li, Mohamed Haloul, Wen Gu, Brandon Faubert, Akash K Kaushik, Ling Cai, Sahba Kasiri, Ummay Marriam, Kien Nham, Luc Girard, Hui Wang, Xiankai Sun, James Kim, John D Minna, Keziban Unsal-Kacmaz, Ralph J DeBerardinis
• Journal: Nature metabolism (Nat Metab) Vol. 2 Issue 12 Pg. 1401-1412 (12 2020) ISSN: 2522-5812 [Electronic] Germany
• PMID: 33257855 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Hexosamines
• KRAS protein, human
• Azaserine
• GFPT2 protein, human
• Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)
• Protein Serine-Threonine Kinases
• STK11 protein, human
• AMP-Activated Protein Kinase Kinases
• Proto-Oncogene Proteins p21(ras)

Topics

• AMP-Activated Protein Kinase Kinases
• Animals
• Antineoplastic Agents (pharmacology)
• Azaserine (therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, mortality)
• Cell Line, Tumor
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation, Neoplastic
• Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) (antagonists & inhibitors, genetics)
• Hexosamines (biosynthesis)
• Humans
• Lung Neoplasms (drug therapy, genetics, mortality)
• Metabolic Networks and Pathways
• Metabolomics
• Mice
• Mutation
• Protein Serine-Threonine Kinases (genetics)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Survival Analysis
• Tumor Stem Cell Assay