Whole genome doubling confers unique genetic vulnerabilities on tumor cells

Whole genome doubling (WGD) occurs early in tumorigenesis and generates genetically unstable tetraploid cells that fuel tumor development(1,2). Cells that undergo WGD (WGD(+)) must adapt to accommodate their abnormal tetraploid state; however, the nature of these adaptations, and whether they confer vulnerabilities that can subsequently be exploited therapeutically, is unclear. Using sequencing data from ~10,000 primary human cancer samples and essentiality data from ~600 cancer cell lines, we show that WGD gives rise to common genetic traits that are accompanied by unique vulnerabilities. We reveal that WGD(+) cells are more dependent on spindle assembly checkpoint signaling, DNA replication factors, and proteasome function than WGD(–) cells. We also identify KIF18A, which encodes for a mitotic kinesin, as being specifically required for the viability of WGD(+) cells. While loss of KIF18A is largely dispensable for accurate chromosome segregation during mitosis in WGD(–) cells, its loss induces dramatic mitotic errors in WGD(+) cells, ultimately impairing cell viability. Collectively, our results reveal new strategies to specifically target WGD(+) cancer cells while sparing the normal, non-transformed WGD(–) cells that comprise human tissue.