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

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

  • Cell Rep. 2022 Mar 1;38(9):110448. doi: 10.1016/j.celrep.2022.110448.
Erik S Knudsen 1 Vishnu Kumarasamy 2 Ram Nambiar 2 Joel D Pearson 3 Paris Vail 2 Hanna Rosenheck 2 Jianxin Wang 4 Kevin Eng 4 Rod Bremner 3 Daniel Schramek 3 Seth M Rubin 5 Alana L Welm 6 Agnieszka K Witkiewicz 7
Affiliations

Affiliations

  • 1 Department of Molecular and Cellular Biology, Roswell Park Cancer Center, Buffalo, NY 14203, USA. Electronic address: erik.knudsen@roswellpark.org.
  • 2 Department of Molecular and Cellular Biology, Roswell Park Cancer Center, Buffalo, NY 14203, USA; Department of Cancer Genetics and Genomics, Roswell Park Cancer Center, Buffalo, NY 14203, USA.
  • 3 Lunenfeld Tanenbaum Research Institute, Toronto, ON M5G 1X5, Canada.
  • 4 Department of Cancer Genetics and Genomics, Roswell Park Cancer Center, Buffalo, NY 14203, USA.
  • 5 Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
  • 6 Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
  • 7 Department of Cancer Genetics and Genomics, Roswell Park Cancer Center, Buffalo, NY 14203, USA; Department of Pathology, Roswell Park Cancer Center, Buffalo, NY 14203, USA. Electronic address: agnieszka.witkiewicz@roswellpark.org.
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.

Keywords

CDK; E2F; RB; cyclin; cyclin D1; cyclin E; p16; p27.

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