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

Reece Foy, Lisa Crozier, Aanchal U. Pareri, Juan Manuel Valverde, Ben Ho Park, Tony Ly, Adrian T. Saurin (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


CDK4/6 inhibitors are remarkable anti-cancer drugs that can arrest tumor cells in G1 and induce their senescence while causing only relatively mild toxicities in healthy tissues. How they achieve this mechanistically is unclear. We show here that tumor 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 progression from G1 or inducing 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 the cells to CDK4/6 inhibition. Together, this demonstrates that cell cycle arrest and oncogenic cell growth is a synthetic lethal combination that is exploited by CDK4/6 inhibitors to induce tumor-specific toxicity.
Original languageEnglish
Pages (from-to)4047-4061.e6
Number of pages21
JournalMolecular Cell
Issue number22
Publication statusPublished - 16 Nov 2023


  • CDK4/6
  • oncogenes
  • cell growth
  • cell cycle
  • growth factors
  • chemotherapy
  • breast cancer
  • p53
  • p21
  • replication stress


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