Targeting metabolic dependencies in cancer cells in vitro

Abstract

Lung adenocarcinoma (LUAD) is a prevalent and aggressive form of lung cancer. Targeting metabolic pathways, particularly the serine and glycine biosynthesis pathways, represents a promising therapeutic strategy. Phosphoglycerate dehydrogenase (PHGDH), a key enzyme in serine biosynthesis, is frequently overexpressed in LUAD. NCT-503, a PHGDH inhibitor, has emerged as a potential therapeutic agent against LUAD.

This study aimed to evaluate the efficacy of NCT-503 in inhibiting cancer cell viability and altering metabolic pathways in LUAD cell lines. Cell Titer Glow (CTG) assays were employed to assess cell viability across varying drug concentrations, while uptake assays measured the absorption and secretion of serine and glycine in treated and untreated cells. Experiments were conducted on two LUAD cell lines, A1 and Y2, representing elder and younger populations, respectively.

CTG assays revealed a dose-dependent response to NCT-503, with significant cell viability reduction at higher drug concentrations (200 µM). Interestingly, the A1 cell line showed higher sensitivity to lower concentrations (<100 µM) compared to Y2. Uptake assays presented complex and varied responses; Y2 cells exhibited decreased serine secretion and glycine absorption post-treatment, while A1 cells showed increased secretion of these metabolites. Notably, the patterns of nutrient uptake were inconsistent across different trials, indicating potential variability in cellular responses to NCT-503.

The study confirmed that PHGDH inhibition by NCT-503 effectively hinders cancer cell growth, particularly in the A1 cell line. However, the discrepancies between CTG and uptake assays highlight the complexity of cellular metabolic responses. Variability in results suggests the need for further investigation to ensure reliability and reproducibility. Factors such as cell age, genetics, and experimental conditions may influence the drug’s efficacy. The study highlights the necessity for ongoing research, including repeated uptake assays, intracellular metabolite analysis, and in vivo trials, to validate NCT-503's therapeutic potential and ensure minimal side effects.

NCT-503 shows promise as a therapeutic agent against LUAD, particularly for elder patients, by effectively inhibiting cancer cell viability through PHGDH inhibition. However, the complexity of cellular responses and potential laboratory errors necessitate further research to confirm these findings and optimize treatment protocols.