Abstract
Genotoxic chemotherapies are central components of the treatment regimen for most cancers but are rarely curative. Drug-tolerant persister cells (DTPs) evade cell death during these treatments by accessing transient adaptive states, allowing them to contribute to cancer progression after treatment. Here, we demonstrate that cancer cells can survive genotoxic chemotherapy-induced stress by accessing a previously undescribed DTP state where mitotic bypass and continued endocycling promote survival by allowing cells to evade mitotic catastrophe and cell death. Mechanistic studies indicate that mitotic bypass is dependent on CDK1 inhibition by WEE1 and Myt1, which prevents entry into mitosis and induces premature APC/C activation during G2 arrest. Disrupting WEE1 or Myt1 activity using clinical-stage small molecule inhibitors promotes CDK1 reactivation, forcing mitotic entry, catastrophe, and cell death. Our results identify mitotic bypass and endocycling as a targetable mediator of cancer cell persistence that can be exploited for the eradication of DTPs.