Therapeutic CDK4/6 inhibition in breast cancer and the importance of reestablishing cell cycle control through RB activation
A functional RB/E2F pathway is requisite for maintenance of genome integrity and orderly cell cycle progression. As such, functional inactivation of the RB/E2F signaling axis occurs in the majority of human cancers, resulting in a disconnect of mitogenic signaling from cell cycle regulation. At the most basic level, such functional inactivation results in increased rates of cell cycle progression. However, it is currently unknown how increased proliferation translates to biological consequence in regards to tumor initiation and progression. Herein, we have examined the ability of genetic RB loss to cooperate with several prominent oncogenes and promote characteristics relevant to human tumor biology. As described, the effects of RB1 deletion were highly context dependant and exacerbated in the presence of cellular stresses that occur during tumorigenesis. With an increased understanding of the importance of retaining a functional RB/E2F pathway, a small molecule CDK4/6 inhibitor was employed to determine the utility of RB activation in the treatment of breast cancer. Again, a varied requirement for RB/E2F/cyclin D activity was observed. While durable cytostatic response was achieved in specific settings, it was also observed that therapeutic bypass can be achieved through redundancies in cyclin/CDK biology. Furthermore, as CDK4/6 inhibitors are currently undergoing phase I/II clinical study there is a clear need to understand how they can cooperate with current standard of care therapies. Through combination exposure of breast cancer cells to CDK4/6 inhibition and chemotherapeutic agents which are known to require active cell cycle for maximal effect, it was observed that CDK4/6 inhibition could modify the acute cell cycle and biochemical response to chemotherapy. In response to gamma-irradiation, overall rates of DNA break repair were not altered. However, a significant shift to the use of error-prone DNA repair pathways was observed through RB-dependent decreases in Rad51 protein. Together, these data illustrate a context-dependant requirement for functional RB protein; a characteristic that can be exploited through the clinical application of CDK4/6 inhibitors. However, before such agents reach widespread clinical application, consideration of the proximal cell cycle and transcriptional effects of such agents much be undertaken to derive maximum therapeutic benefit.
0379: Cellular biology