Cancer recurrence and lethality are enabled by enhanced survival and reversible cell cycle arrest of polyaneuploid cells.

We present a unifying theory to explain cancer recurrence, therapeutic resistance, and lethality. The basis of this theory is the formation of simultaneously polyploid and aneuploid cancer cells, polyaneuploid cancer cells (PACCs), that avoid the toxic effects of systemic therapy by entering a state of cell cycle arrest. The theory is independent of which of the classically associated oncogenic mutations have already occurred. PACCs have been generally disregarded as senescent or dying cells. Our theory states that therapeutic resistance is driven by PACC formation that is enabled by accessing a polyploid program that allows an aneuploid cancer cell to double its genomic content, followed by entry into a nondividing cell state to protect DNA integrity and ensure cell survival. Upon removal of stress, e.g., chemotherapy, PACCs undergo depolyploidization and generate resistant progeny that make up the bulk of cancer cells within a tumor.