Mutant KRAS–driven NSCLC depends on branched-chain amino acid metabolism, whereas PDAC does not.
Major finding: Mutant KRAS–driven NSCLC depends on branched-chain amino acid metabolism, whereas PDAC does not.
Concept: Tissue of origin affects the metabolic dependencies of tumors driven by the same genetic events.
Impact: Tissue-specific metabolic dependencies and mutation status may guide treatment of patients with cancer.
Mutations activating KRAS and inactivating TP53 occur in multiple tumor types including pancreatic ductal adenocarcinoma (PDAC) and non–small cell lung carcinoma (NSCLC) and can induce metabolic changes. To determine the influence of tumor type on metabolic dependencies, Mayers, Torrence, and colleagues looked at the metabolism of branched-chain amino acids (BCAA) in mouse models of PDAC and NSCLC both driven by Kras mutation and Trp53 deletion. Similar to previous findings, mice with PDAC had elevated plasma BCAA levels; however, in NSCLC, plasma BCAA levels were reduced. PDACs displayed reduced levels of free BCAAs compared with normal pancreas whereas NSCLC tumors exhibited increased BCAAs compared with normal lung, suggesting that NSCLCs have increased BCAA uptake. NSCLCs also showed increased incorporation of BCAAs into proteins and elevated α-ketoisocaproate, which is generated by transamination of the BCAA leucine by BCAA transaminase (BCAT). Further, BCAAs served as a nitrogen source in NSCLCs with BCAA-derived nitrogen incorporation into aspartate and nucleotides, suggesting that BCAAs may support nucleotide biosynthesis and proliferation in the lung when aspartate is limiting. Consistent with these findings, NSCLC tumors had increased expression of the BCAA transporter Slc7a5, as well as the metabolic enzymes Bcat2 and Bckdh, which enable the use of BCAAs as a nitrogen source, whereas PDACs exhibited decreased expression of these genes. Analysis of human gene expression data revealed similar expression of BCAA catabolic enzymes in patients with NSCLC and PDAC, even though KRAS and TP53 mutations occur in less than half of human NSCLCs. Moreover, in orthotopic transplantations Bcat-deficient PDAC cells formed tumors whereas Bcat-deficient NSCLC cells failed to do so. In addition to demonstrating that NSCLCs depend on BCAT-dependent BCAA metabolism, these findings indicate that the tissue of origin alters tumor metabolism even in tumors with the same underlying driver mutations and that unique metabolic dependencies may have potential in guiding treatment approaches in patients.