A Lung Cancer Subtype Depends on the Hexosamine Biosynthesis Pathway

Mutations in KRAS and LKB1 (also known as STK11) are common in non–small cell lung cancer (NSCLC) and confer an aggressive and highly metastatic phenotype, and comutation of these two genes is known to cause metabolic aberrations that may be targetable vulnerabilities. In search of additional metabolic liabilities in KRAS/LKB1-comutant NSCLC, Kim and colleagues generated a genetically engineered mouse model (GEMM) of Kras/Lkb1-comutant NSCLC and compared it with a GEMM of Kras/Trp53-comutant NSCLC and a GEMM of NSCLC with Kras mutation alone. Metabolomic analyses revealed that compared with the two other tumor types, the Kras/Lkb1-comutant lung tumors had altered metabolism of amino sugars and nucleotide sugars along with perturbations in the fructose and mannose pathways, all of which converge on the hexosamine biosynthesis pathway (HBP). Upregulation of the HBP was also observed in human KRAS/LKB1-comutant NSCLC cells in vitro, but not cells with KRAS mutation alone, increasing intracellular O-GlcNAcylation, the reversible covalent linkage of an N-acetyl-glucosamine residue (GlcNAc) to a serine or threonine residue of a protein. KRAS/LKB1-comutant NSCLC cells engineered to express wild-type (WT) LKB1 exhibited reduced protein glycosylation, an effect also attributable to reduced flux through the HBP in LKB1-WT versus LKB1-mutant cells. Notably, KRAS/LKB1-comutant NSCLC cells had increased dependence on the HBP enzyme GFPT2 in human NSCLC cells and tumor xenografts, as did Kras/Lkb1-mutant lung tumors in NSCLC GEMMs. In summary, this work identifies the HBP as a vulnerability specific to KRAS/LKB1-comutant NSCLC and suggests that this tumor type may be responsive to GFPT2 inhibition.

Kim J, Lee HM, Cai F, Ko B, Yang C, Lieu EL, et al. The hexosamine biosynthesis pathway is a targetable liability in KRAS/LKB1 mutant lung cancer. Nat Metab 2020 Nov 30 [Epub ahead of print].

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