KIF2C promotes paclitaxel resistance by depolymerizing polyglutamylated microtubules.

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Paclitaxel effectiveness is limited by chemoresistance in triple-negative breast cancer (TNBC).
• Kinesin family member 2C (KIF2C) is a microtubule depolymerase implicated in cancer progression.

Purpose of the Study:

• To elucidate the molecular mechanism of KIF2C in paclitaxel chemoresistance in TNBC.
• To evaluate KIF2C as a therapeutic target for overcoming chemoresistance.

Main Methods:

• Assessed KIF2C, tubulin tyrosination, and polyglutamylation levels in paclitaxel-resistant TNBC cells.
• Developed and tested 7S9, a KIF2C inhibitor, in combination with paclitaxel in mouse models.
• Investigated KIF2C's interaction with polyglutamylated tubulin.

Main Results:

• Elevated KIF2C, tubulin tyrosination, and polyglutamylation were observed in chemoresistant TNBC cells.
• KIF2C preferentially depolymerizes polyglutamylated tubulin, conferring cross-resistance to various microtubule-targeting agents (MTAs).
• Combination therapy with 7S9 and paclitaxel significantly reduced tumor growth in chemoresistant TNBC mouse models and diminished chemoresistance to clinically available MTAs.

Conclusions:

• KIF2C mediates chemoresistance in TNBC by targeting polyglutamylated tubulin.
• KIF2C inhibition represents a promising strategy to combat paclitaxel resistance and cross-resistance in TNBC.
• 7S9 demonstrates potential as an adjunct therapy for chemoresistant TNBC.