Delineating the dystopian nature of the cell cycle in cancer

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ABSTRACT: In the classical mammalian cell cycle model, CDK and cyclin complexes are responsible for driving specific events in a sequential fashion. Mitogenic or oncogenic signals drive the activation of CDK4/6 complexes that initiate cell cycle progression. These complexes promote RB phosphorylation that leads to the expression of a highly conserved cadre of genes that are required for progression through the remainder of the cell cycle. The concept put forward by this model is that cell cycle control is linear and highly predictable. However, recent findings related to the inter-dependencies of CDK/cyclins illustrate the need for better understanding the cell cycle repertoires that are operable in tumors. In preliminary data using unbiased and targeted approaches we have interrogated the extent to which the “utopian” simple version of the cell cycle breaks-down. This work indicates that in cancer models there are multiple different cell cycle modes, which have significance for tumorigenic proliferation and therapeutic interventions. Here we will take an integrated approach to fundamentally understand “dystopian” cell cycle states (Aim 1) and define mechanisms of collateral therapeutic resistance and new vulnerabilities (Aim 2) which associate with non-canonical cell cycle states.