Pareri, A. U. | Search bioRxiv

bioRxiv2025

Cell enlargement causes mitotic errors and aneuploidy in cells that evade senescence after CDK4/6 inhibition

AO_SCPLOWBSTRACTC_SCPLOWCDK4/6 inhibitors (CDK4/6i) arrest the cell cycle in G1 leading to cellular overgrowth and p53-dependent senescence. They are used to treat metastatic HR+/HER2-breast cancer, but resistance is common, and this has been associated with TP53 loss and senescence evasion. We show here that enlarged CDK4/6i-treated cells that evade senescence mis-segregate chromosomes due to defective chromosomal alignment and a weakened mitotic checkpoint, leading to aneuploidy and DNA damage. The chromosome alignment errors are associated with impaired Sgo1 localisation to centromeres and defective sister chromatin cohesion during mitosis. Importantly, all these mitotic defects can be rescued by constraining cell size during the CDK4/6i-treatment, and specifically restoring cohesion rescues the chromosome segregation errors. Together, this demonstrates mechanistically how cell enlargement drives genetic and karyotypic change in cells that re-enter the cell cycle following CDK4/6 inhibition. This could help fuel the rapid emergence of chemotherapy-resistant clones, especially in p53-null cells that evade senescence to drive drug-resistance in patients.

cancer biology↗

bioRxiv2022

Oncogenic signals prime cancer cells for toxic cell growth during a G1 cell cycle arrest

A long-term goal in cancer research has been to inhibit the cell cycle in tumour cells without causing toxicity in proliferative healthy tissues. The best evidence that this is achievable is provided by CDK4/6 inhibitors, which arrest the cell cycle in G1, are well-tolerated in patients, and are effective in treating ER+/HER2-breast cancer. CDK4/6 inhibitors are effective because they arrest tumour cells more efficiently than some healthy cell types and, in addition, they affect the tumour microenvironment to enhance anti-tumour immunity. We demonstrate here another reason to explain their efficacy. Tumour cells are specifically vulnerable to CDK4/6 inhibition because during the G1 arrest, oncogenic signals drive toxic cell overgrowth. This overgrowth causes permanent cell cycle withdrawal by either preventing exit from G1 or by inducing replication stress and genotoxic damage during the subsequent S-phase and mitosis. Inhibiting or reverting oncogenic signals that converge onto mTOR can rescue this excessive growth, DNA damage and cell cycle exit in cancer cells. Conversely, inducing oncogenic signals in non-transformed cells can drive these toxic phenotypes and sensitize cells to CDK4/6 inhibition. Together, this demonstrates how oncogenic signals that have evolved to stimulate constitutive tumour growth and proliferation can be driven to cause toxic cell growth and irreversible cell cycle exit when proliferation is halted in G1.

cancer biology↗