FGF13 enhances resistance to platinum drugs by regulating hCTR1 and ATP7A via a microtubule-stabilizing effect

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Platinum-based chemotherapy is a cornerstone of cancer treatment.
• Acquired resistance to platinum drugs significantly limits therapeutic efficacy.
• Fibroblast growth factor 13 (FGF13) has been previously linked to platinum resistance in specific cell lines.

Purpose of the Study:

• To elucidate the mechanism and universality of FGF13-mediated platinum resistance across various cancer types.
• To investigate the role of FGF13 in regulating platinum drug transport.
• To determine if FGF13's microtubule-stabilizing function is essential for platinum resistance.

Main Methods:

• Bioinformatics analysis of FGF13 expression in relation to chemotherapy outcomes in lung, endometrial, and cervical cancers.
• Cellular assays to assess platinum influx, sequestration, and efflux in response to FGF13.
• Mutational analysis of the FGF13 tubulin-binding domain to assess its role in platinum resistance.
• Validation in multiple cancer cell lines (SK-MES-1, KLE, 5637).

Main Results:

• FGF13 expression correlates with poor platinum-based chemotherapy outcomes in multiple cancer types.
• FGF13 regulates the expression and distribution of hCTR1 and ATP7A, reducing platinum influx and promoting sequestration/efflux.
• FGF13-induced platinum resistance is dependent on its microtubule-stabilizing activity, specifically requiring the -SMIYRQQQ- tubulin-binding domain.
• The observed resistance mechanism is consistent across different cancer cell lines.

Conclusions:

• FGF13 is a key mediator of platinum drug resistance in various cancers.
• The mechanism involves altered platinum transport via regulation of hCTR1 and ATP7A, dependent on FGF13's microtubule-stabilizing function.
• FGF13 represents a potential therapeutic target for overcoming platinum resistance and a valuable prognostic biomarker.