Microtubule-targeting agents (MTAs) are standard of care for a number of human malignancies including blood, breast, ovarian and lung cancer. Their mode of action includes prolonged mitotic arrest by interfering with mitotic spindle dynamics that leads to the activation of the spindle assembly checkpoint (SAC). SAC execution involves assembly of the mitotic checkpoint complex (MCC) containing MAD2, Bub3 and BubR1 at kinetochores, driving degradation of the Anaphase-promoting complex (APC) co-activator, CDC20, thereby preventing mitotic exit. Cells stalled in mitosis usually can undergo two different fates, either cell death involving the BH3-only proteins BIM, BID and NOXA that can be paralleled by Ripoptosome activation, or, alternatively, checkpoint adaptation (slippage). The latter occurs when CyclinB levels fall below a critical threshold, due to non-canonical APC-driven protein degradation, that often correlates with a concomitant reduction of pro-apoptotic mediators of the BCL2 family. This leads to premature mitotic exit and escape from apoptosis, often in a polyploid state. Such cells are well known to become genetically instable due to unfaithful segregation of chromosomes leading to chromosomal instability (CIN). The fate of such chromosomally instable (cancer) cells is usually regulated by the tumor suppressor p53 and its activation can either result in post-mitotic cell death, by so-far poorly defined molecular mechanisms (mitotic catastrophe), or cellular senescence. In the absence of p53, such cells can escape these control mechanisms, leading to the creation and expansion of aneuploid clones that form the basis of tumor evolution, progressive disease and ultimately also drug-resistance.
The aim of this proposal is to (i) define the mechanisms controlling activity of BH3-only proteins relevant in mitotic and post-mitotic cell death and to (ii) interrogate the contribution of BCL2-regulated cell death in and out of mitosis as a barrier against aneuploidy and cancer.