Mitotic Spindle Assembly and Genomic Stability in Breast Cancer Require PI3K-C2α 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 \uce\ub1 (PI3K-C2\uce\ub1) acting as limiting scaffold protein organizing clathrin and TACC3 complex crosslinking K-fibers. Downregulation of PI3K-C2\uce\ub1 causes spindle alterations, delayed anaphase onset, and aneuploidy, indicating that PI3K-C2\uce\ub1 expression is required for genomic stability. Reduced abundance of PI3K-C2\uce\ub1 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\uce\ub1 increases sensitivity to taxane-based therapy in pre-clinical models and in neoadjuvant settings. Gulluni et al. reveal a kinase-independent scaffolding function of PI3K-C2\uce\ub1 that affects mitotic spindle formation. Reduced levels of PI3K-C2\uce\ub1 reduce tumor growth initially but provide a growth advantage later in mouse models of breast cancer. Loss of PI3K-C2\uce\ub1 also increases sensitivity of tumors to taxanes