Chromosomally unstable tumor cells specifically require KIF18A for proliferation

Chromosomal instability (CIN), characterized by frequent missegregation of chromosomes during mitosis, is a hallmark of tumor cells caused by changes in the dynamics and control of microtubules that comprise the mitotic spindle. Thus, CIN tumor cells may respond differently than normal diploid cells to treatments that target mitotic spindle regulation. We tested this idea by inhibiting a subset of kinesin motor proteins that control spindle microtubule dynamics and mechanics but are not required for the proliferation of near-diploid cells. Our results indicate that KIF18A is required for proliferation of CIN cells derived from triple negative breast cancer or colorectal cancer tumors but not normal breast epithelial cells or near-diploid colorectal cancer cells exhibiting microsatellite instability. CIN tumor cells exhibit mitotic delays, multipolar spindles due to centrosome fragmentation, and increased cell death following inhibition of KIF18A. These mitotic defects were further enhanced by increasing the activity of the microtubule depolymerizing kinesin KIF2C/MCAK and are reminiscent of the phenotypes that result from clinically relevant doses of the chemotherapeutic drug paclitaxel. Our results indicate that the altered spindle microtubule dynamics characteristic of CIN tumor cells can be exploited to reduce their proliferative capacity.