Linoleic Acid Reduces Paclitaxel Chemosensitivity in Colorectal Cancer

Area of Science:

• Metabolomics
• Cancer Biology
• Pharmacology

Background:

• Paclitaxel is a key plant-derived anticancer drug used for solid tumors.
• Colorectal cancer (CRC) patients exhibit varied responses to paclitaxel, especially those resistant to 5-fluorouracil (5-FU).
• Understanding metabolic factors is crucial for predicting paclitaxel efficacy in CRC.

Purpose of the Study:

• To identify metabolic determinants of heterogeneous paclitaxel response in colorectal cancer.
• To discover serum metabolites associated with therapeutic outcomes in CRC patients treated with paclitaxel.

Main Methods:

• Integrated serum metabolomic profiling of patient-derived tumor organoids (PDTOs).
• Drug sensitivity assays and in vivo validation using mouse xenograft models.
• Targeted metabolomic quantification and pathway enrichment analysis.

Main Results:

• Linoleic acid (LA) was identified as a serum metabolite inversely correlated with paclitaxel sensitivity.
• Elevated LA levels impaired paclitaxel's ability to induce G2/M cell cycle arrest and reduce cytotoxicity.
• LA was shown to attenuate paclitaxel's antitumor effects by modulating microtubule dynamics, indicating a metabolism-mediated chemoresistance mechanism.

Conclusions:

• Serum linoleic acid is a potential biomarker for paclitaxel resistance in colorectal cancer.
• Metabolic factors significantly influence chemotherapy response in CRC.
• LA may aid in stratifying CRC patients for paclitaxel-based therapies.