Paclitaxel resistance-associated metabolic events in ovarian cancer cells

The standard first-line management of advanced ovarian cancer (OC) comprises cytoreductive (debulking) surgery followed by platinum-based chemotherapy, most commonly a combination of carboplatin and paclitaxel (PTX). However, the development of resistance to PTX frequently compromises treatment efficacy, resulting in disease recurrence and poorer clinical outcomes. Although the metabolic mechanisms underlying carboplatin resistance have been extensively characterised, the specific metabolic alterations contributing to PTX resistance remain poorly understood.

We applied untargeted metabolomics to systematically characterise PTX resistance-associated metabolic reprogramming in OC, aiming to identify targetable vulnerabilities to enhance the platinum-taxane efficacy.

Using an isogenic in vitro model of acquired PTX-resistance (OVCAR8 PTX) and its parental counterpart (OVCAR8 PAR), we analysed intracellular (endometabolome) and extracellular (exometabolome) metabolites via gas chromatography-mass spectrometry (GC-MS).

Multivariate and univariate analyses (│effect size│ ≥ 1.4, p-value ≤ 0.01) revealed a distinct metabolic signature in the endometabolome of PTX-resistant cells. These cells exhibited significantly elevated levels of glycine, myo-inositol, pyroglutamate, proline and taurine, alongside reduced levels of glycerol, glucose and glutamate. Pathway analysis identified putative alterations in redox regulation (glutathione metabolism), energy metabolism (galactose and glyoxylate/dicarboxylate metabolism), amino acid metabolism (arginine and proline), and osmotic stress pathways (taurine and hypotaurine metabolism).

The identified metabolic signature highlights dysregulated pathways (e.g., glutathione metabolism, taurine and hypotaurine metabolism) that may be actionable targets for reversing PTX resistance. Pharmacological modulation of these pathways could restore chemosensitivity, providing a rational strategy to improve platinum-taxane efficacy in advanced OC.