Cell enlargement causes mitotic errors and aneuploidy in cells that evade senescence after CDK4/6 inhibition
AO_SCPLOWBSTRACTC_SCPLOWCDK4/6 inhibitors (CDK4/6i) arrest the cell cycle in G1 leading to cellular overgrowth and p53-dependent senescence. They are used to treat metastatic HR+/HER2-breast cancer, but resistance is common, and this has been associated with TP53 loss and senescence evasion. We show here that enlarged CDK4/6i-treated cells that evade senescence mis-segregate chromosomes due to defective chromosomal alignment and a weakened mitotic checkpoint, leading to aneuploidy and DNA damage. The chromosome alignment errors are associated with impaired Sgo1 localisation to centromeres and defective sister chromatin cohesion during mitosis. Importantly, all these mitotic defects can be rescued by constraining cell size during the CDK4/6i-treatment, and specifically restoring cohesion rescues the chromosome segregation errors. Together, this demonstrates mechanistically how cell enlargement drives genetic and karyotypic change in cells that re-enter the cell cycle following CDK4/6 inhibition. This could help fuel the rapid emergence of chemotherapy-resistant clones, especially in p53-null cells that evade senescence to drive drug-resistance in patients.