Mitotic Spindle Assembly and Genomic Stability in Breast Cancer Require PI3K-C2 alpha Scaffolding Function

Proper organization of the mitotic spindle is key to genetic stability, but molecular components of inter-microtubule bridges that crosslink kinetochore fibers (K-fibers) are still largely unknown. Here we identify a kinase-independent function of class II phosphoinositide 3-OH kinase alpha (PI3K-C2 alpha) acting as limiting scaffold protein organizing clathrin and TACC3 complex crosslinking K-fibers. Downregulation of PI3K-C2 alpha causes spindle alterations, delayed anaphase onset, and aneuploidy, indicating that PI3K-C2 alpha expression is required for genomic stability. Reduced abundance of PI3K-C2 alpha in breast cancer models initially impairs tumor growth but later leads to the convergent evolution of fast-growing clones with mitotic checkpoint defects. As a consequence of altered spindle, loss of PI3K-C2 alpha increases sensitivity to taxane-based therapy in pre-clinical models and in neoadjuvant settings.