KIF2C promotes paclitaxel resistance by depolymerizing polyglutamylated microtubules

The long-term effectiveness of paclitaxel is limited by chemoresistance. In this study, we elucidate the molecular mechanism by which kinesin family member 2C (KIF2C), a well-known microtubule depolymerase, contributes to the development of chemoresistance in triple-negative breast cancer (TNBC). We observed elevated levels of KIF2C, tubulin tyrosination, and polyglutamylation in human and mouse breast cancer cells resistant to paclitaxel. Additionally, these chemoresistant cells possessed cross-resistance to diverse microtubule-targeting agents (MTAs). We demonstrated that KIF2C preferentially depolymerizes polyglutamylated tubulin, even in the presence of paclitaxel. To counter this, we developed 7S9, a chemical inhibitor of KIF2C, that prohibits the dissociation of KIF2C from microtubules. The combination of 7S9 and paclitaxel significantly reduced tumorigenesis in chemoresistant TNBC model in mice. Moreover, 7S9 diminished cancer cell chemoresistance to several clinically available MTAs. Our findings elucidate the molecular mechanism of KIF2C-mediated chemoresistance and highlight KIF2C as a promising target for combating cross-resistance in TNBC.