CDK/cyclin dependencies define extreme cancer cell-cycle heterogeneity and collateral vulnerabilities

Erik S. Knudsen, Vishnu Kumarasamy, Ram Nambiar, Joel D. Pearson, Paris Vail, Hanna Rosenheck, Jianxin Wang, Kevin Eng, Rod Bremner, Daniel Schramek, Seth M. Rubin, Alana L. Welm, Agnieszka K. Witkiewicz

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Progression through G1/S phase of the cell cycle is coordinated by cyclin-dependent kinase (CDK) activities. Here, we find that the requirement for different CDK activities and cyclins in driving cancer cell cycles is highly heterogeneous. The differential gene requirements associate with tumor origin and genetic alterations. We define multiple mechanisms for G1/S progression in RB-proficient models, which are CDK4/6 independent and elicit resistance to FDA-approved inhibitors. Conversely, RB-deficient models are intrinsically CDK4/6 independent, but exhibit differential requirements for cyclin E. These dependencies for CDK and cyclins associate with gene expression programs that denote intrinsically different cell-cycle states. Mining therapeutic sensitivities shows that there are reciprocal vulnerabilities associated with RB1 or CCND1 expression versus CCNE1 or CDKN2A. Together, these findings illustrate the complex nature of cancer cell cycles and the relevance for precision therapeutic intervention.

Original languageEnglish (US)
Article number110448
JournalCell Reports
Volume38
Issue number9
DOIs
StatePublished - Mar 1 2022
Externally publishedYes

Keywords

  • CDK
  • E2F
  • RB
  • cyclin
  • cyclin D1
  • cyclin E
  • p16
  • p27

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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