# Tick-Tock: Cancer Cell Division Cycle Clocks Strike Midnight

## TL;DR

The paper suggests that disrupting cancer cell division cycles could increase proteotoxic stress and potentially improve cancer treatment.

## Contribution

A novel hypothesis proposing that targeting the APC/C in combination with HSP90 inhibitors could exploit proteotoxic stress in cancer cells.

## Key findings

- Cancer cells may be more sensitive to forced overgrowth due to proteotoxic stress.
- Combining APC/C suppression with HSP90 inhibition could disrupt cancer cell function.
- This specific combination of treatments has not been previously investigated.

## Abstract

Eukaryotic cells double their mass and divide at the same rate, allowing cells to maintain a uniform cell size over many cell divisions. We hypothesize that aneuploid cancer cells are more sensitive to forced overgrowth, more than doubling their mass during a single longer-duration cell division cycle, relative to healthy diploid cells. This hypothesis stems from the observation that cancer cells are under proteotoxic stress, during which heat-shock proteins become rate-limiting and the unfolded-protein response network has a growth-suppressive phenotype. Forced overgrowth will lead to the production of more individual proteins per cell division cycle and increase the duration of time during which any mis-folded or aggregated proteins might disrupt the function of properly folded proteins. To induce these potential forced overgrowth effects, we suggest targeting the cell division cycle regulatory enzyme, the anaphase-promoting complex/cyclosome (APC/C), to suppress—but not inhibit—its activity. We conclude by proposing experiments to test this hypothesis in which an APC/C inhibitor, such as a low level of proTAME, is combined with the clinically approved heat-shock protein 90 (HSP90)-inhibitor pimitespib (TAS-116) or the pre-clinical molecule tanespimycin, which, to the best of our knowledge, are combinations that have not been investigated before.