Metabolic liabilities in cancer cells provide the opportunity for novel therapeutic approaches. This is especially true as the dogma that all cancer cells are glycolytic is being challenged. Phenotypic screening of cancer cell lines can demonstrate what these liabilities are and suggest approaches for drugs that target these vulnerabilities. As an example, non-small cell lung cancer (NSCLC) is typically driven by oncogenic mutations in either KRAS or EGFR. However, the impact of these mutations on cellular metabolic phenotype is not well-studied. In this study, we observed that the two KRAS-mutated NSCLC cell lines (A549 and H460) primarily relied on glycolysis for ATP production while EGFR-mutated cell lines (H1975 and PC9) were more reliant on mitochondrial respiration to meet energy demands. There is emerging evidence to suggest that lactate is a major fuel for cancer cell energy metabolism especially in the glucose-limited tumor microenvironment. Thus, we next compared the use of lactate with other carbon sources for ATP production in NSCLC cells. We found there was differential usage of lactate for mitochondrial respiration between KRAS and EGFR-mutated NSCLC cells. EGFR-mutated NSCLC cells used lactate and increased mitochondrial respiration when lactate was acutely administrated regardless of glucose availability. In contrast, the use of lactate for the mitochondrial respiration by KRAS-mutated cells was limited. In A549 cells, no significant change in mitochondrial respiration rate was observed at all by acute injection of lactate. Together, these results imply that NSCLC variants have adopted different metabolic phenotypes depending on the oncogenic background and more oxidative phenotype may be correlated to higher lactate use for TCA cycle in production of ATP.

Citation Format: Pamela Swain, Natalia Romero, Yoonseok Kam, Brian P. Dranka. Differential use of lactate for mitochondria respiration by NSCLC cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 810.