Cell Cycle Plasticity and Heterogeneity: An Underappreciated Feature of Cancer and Treatment Response

Progression through the mammalian cell cycle is a highly regulated process to maintain tissue homeostasis. The key regulators of cell cycle transitions are cyclin-dependent kinase (CDK)/Cyclin complexes that phosphorylate substrates such as the RB tumor suppressor to facilitate cellular division. The regulation of G1/S is of particular significance in cancer and is affected by numerous tumor suppressors and oncogenes. Historically, the cell cycle was viewed as a rigidly regulated process, but recent evidence has revealed significant flexibility and differential CDK/Cyclin dependencies across tumor types. These heterogeneous features of cell cycle control have implications for the etiology of different tumor types as well as the response to multiple therapeutic modalities. Most notably, adaptive responses in cell cycle regulatory circuits can contribute to acquired resistance in a variety of contexts, underscoring the importance for tumor biology and disease treatment.