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Simple Summary: We evaluated the repurposing of a class of non-cancer drugs, phosphodiesterase inhibitors, to increase the potency of an anti-folate chemotherapy drug against non-small-cell lung cancer. We showed that this approach represents a double-edged strategy. While the use of phosphodiesterase inhibitors potentiated the killing of lung cancer cells by combination low-dose anti-folate chemotherapy, in half of the tumors evaluated, the benefit was lost when using higher doses of chemotherapy. Phosphosidesterases (PDEs) are key regulators of cyclic nucleotide signaling, controlling many hallmarks of cancer and playing a role in resistance to chemotherapy in non-small-cell lung cancer (NSCLC). We evaluated the anti-tumor activity of the anti-folate agent pemetrexed (PMX), alone or combined with biochemical inhibitors of PDE5, 8, 9, or 10, against squamous and non-squamous NCSLC cells. Genomic alterations to PDE genes (PDEmut) or PDE biochemical inhibition (PDEi) can sensitize NSCLC to PMX in vitro (observed in 50% NSCLC evaluated). The synergistic activity of PDEi with PMX required microdosing of the anti-folate drug. As single agents, none of the PDEis evaluated have anti-tumor activity. PDE biochemical inhibitors, targeting either cAMP or cGMP signaling (or both), resulted in significant cross-modulation of downstream pathways. The use of PDEi may present a new strategy to overcome PMX resistance of PDEwt NSCLC tumors but comes with important caveats, including the use of subtherapeutic PMX doses. [ABSTRACT FROM AUTHOR]

Background: Metabolomics studies to date have described widespread metabolic reprogramming events during the development of non-squamous non-small cell lung cancer (NSCLC). Extending far beyond the Warburg effect, not only is carbohydrate metabolism affected, but also metabolism of amino acids, cofactors, lipids, and nucleotides., Methods: We evaluated the clinical impact of metabolic reprogramming. We performed comparative analysis of publicly available data on non-squamous NSCLC, to identify concensus altered metabolic pathways. We investigated whether alterations of metabolic genes controlling those consensus metabolic pathways impacted clinical outcome. Using the clinically annotated lung adenocarcinoma (LUAD) cohort from The Cancer Genome Atlas, we surveyed the distribution and frequency of function-altering mutations in metabolic genes and their impact on overall survival (OS)., Results: We identified 42 metabolic genes of clinical significance, the majority of which (37 of 42) clustered across three metabolic superpathways (carbohydrates, amino acids, and nucleotides) and most functions (40 of 42) were associated with shorter OS. Multivariate analyses showed that dysfunction of carbohydrate metabolism had the most profound impact on OS [hazard ratio (HR) =5.208; 95% confidence interval (CI): 3.272 to 8.291], false discovery rate (FDR)-P≤0.0001, followed by amino acid metabolism (HR =3.346; 95% CI: 2.129 to 5.258), FDR-P≤0.0001 and nucleotide metabolism (HR =2.578; 95% CI: 1.598 to 4.159), FDR-P=0.0001. The deleterious effect of metabolic reprogramming on non-squamous NSCLC was observed independently of disease stage and across treatments groups., Conclusions: By providing a detailed landscape of metabolic alterations in non-squamous NSCLC, our findings offer new insights in the biology of the disease and metabolic adaptation mechanisms of clinical significance., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-377/coif). AVIF reports that this work was supported by North Carolina Lung Cancer Initiative Research Fellow grant. The other authors have no conflicts of interest to declare., (2022 Translational Lung Cancer Research. All rights reserved.)