Molecular determinants of cell-to-cell variability in the cellular response to anti-mitotic drugs

Andrea Ciliberto
IFOM, via Adamello 16, Milan


Antimitotic drugs arrest cell proliferation by activating a signaling pathway known as the mitotic checkpoint. When the checkpoint is engaged, it arrests cells before DNA is segregated from the mother to the daughter cells. Cells can maintain an arrest for several hours, but eventually they adapt and resume proliferation. Cell division in the presence of antimitotic drugs is prone to be inefficient, and to increase the genetic variability of cancer cells. Understanding how cells manage to adapt is thus critical to increase the efficiency of antimitotic drugs. At the present stage, however, not much is known about this phenomenon. Especially little is known about the striking variability in adaptation times observed among genetically identical cells. Here, we use a combination of live-cell imaging and mathematical models to show that i) adaptation is an active process; ii) adaptation is stochastic; iii) early and late adapters do not have a stable molecular identity; iv) cells have developed mechanisms to buffer external perturbations that force adaptation.