Chromosomally unstable tumor cells specifically require KIF18A for proliferation

Abstract

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 spindle1-3. 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 indicated that KIF18A was required for proliferation of CIN cells derived from triple negative breast cancer or colorectal cancer tumors but was not required in near-diploid cells. CIN tumor cells exhibited mitotic delays, multipolar spindles due to centrosome fragmentation, and increased cell death following inhibition of KIF18A. Sensitivity to KIF18A knockdown was strongly correlated with centrosome fragmentation, which required dynamic microtubules but did not depend on bipolar spindle formation or mitotic arrest. Our results indicate the altered spindle microtubule dynamics characteristic of CIN tumor cells can be exploited to reduce the proliferative capacity of CIN cells.