The Combination of Loss of ALDH1L1 Function and Phenformin Treatment Decreases Tumor Growth inKRAS-Driven Lung Cancer

Lung adenocarcinoma cells express high levels ofALDH1L1, an enzyme of the one-carbon pathway that catalyzes the conversion of 10-formyltetrahydrofolate into tetrahydrofolate and NAD(P)H. In this study, we evaluated the potential ofALDH1L1as a therapeutic target by deleting theAldh1l1gene inKras(LA2)mice, a model of spontaneous non-small cell lung cancer (NSCLC). Reporter assays revealed KRAS-mediated upregulation of theALDH1L1promoter in human NSCLC cells.Aldh1l1(-/-)mice exhibited a normal phenotype, with a 10% decrease inKras-driven lung tumorigenesis. By contrast, the inhibition of oxidative phosphorylation inhibition using phenformin inAldh1l1(-/-);Kras(LA2)mice dramatically decreased the number of tumor nodules and tumor area by up to 50%. Furthermore, combined treatment with pan-ALDH inhibitor and phenformin showed a decreased number and area of lung tumors by 70% in theKras(LA2)lung cancer model. Consistent with this, previous work showed that the combination ofALDH1L1knockdown and phenformin treatment decreased ATP production by as much as 70% in NSCLS cell lines. Taken together, these results suggest that the combined inhibition of ALDH activity and oxidative phosphorylation represents a promising therapeutic strategy for NSCLC.