Cell enlargement causes mitotic errors and aneuploidy in cells that evade senescence after CDK4/6 inhibition
Pareri, A. U.; Losito, M.; Foijer, F.; Saurin, A. T.
Show abstract
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.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Mild replication stress causes premature centriole disengagement via a sub-critical Plk1 activity under the control of ATR-Chk1 97%
- WEE1 inhibitors trigger GCN2-mediated activation of the integrated stress response 97%
- Sub-centrosomal mapping identifies augmin-γTuRC as part of a centriole-stabilizing scaffold 97%
Similar papers in this journal
- Spindle assembly checkpoint-dependent mitotic delay is required for cell division in absence of centrosomes 96%
- RIF1-Long promotes G1 phase 53BP1 nuclear bodies to protect against replication stress 96%
- Rapid and specific degradation of endogenous proteins in mouse models using auxin-inducible degrons 95%
Similar papers in this journal
- Profilin 1 deficiency drives mitotic defects and impairs genome stability 96%
- Fission yeast Dis1 is an unconventional TOG/XMAP215 that induces microtubule catastrophe to drive chromosome pulling 96%
- Selective targeting of non-centrosomal AURKA functions through use of a targeted protein degradation tool 96%
Similar papers in this journal
Similar papers in this journal
- The mitotic surveillance pathway requires PLK1-dependent 53BP1 displacement from kinetochores 96%
- Alternative splice variants of the mitochondrial fission protein DNM1L/Drp1 regulate mitochondrial dynamics and cell fate in ovarian cancer. 94%
- Drs2 regulates TRAPPIII in Atg9 transport: exposing the interplay of P4-ATPases and Multisubunit Tethering Complexes 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.