Breast cancer is the most diagnosed cancer worldwide and a leading cause of cancer-related deaths in women. Estrogen receptor positive (ER+) breast cancer accounts for more than 70% of all cases. The development and use of endocrine therapies (ET) aimed at inhibiting the ER has demonstrated clinical benefits in ER+ breast cancer. However, some patients are intrinsically resistant to ET and a high proportion of patients will eventually become resistant to ET. This highlights a critical gap in the current management for advanced ER+ breast cancer and the urgent need for the development of alternative targeted therapies. Highly selective inhibitors of cyclin dependent kinases, CDK4 and CDK6 (CDK4/6), namely palbociclib, abemaciclib and ribociclib have been developed and have the potential to change the treatment landscape for advanced breast cancer patients. These CDK4/6 inhibitors (CDK4/6i) demonstrate great clinical efficacy when used in combination with ET. Thus, this therapeutic strategy has been approved by regulatory bodies in many countries as first-line therapy for advanced breast cancer. Despite their clinical success, resistance to CDK4/6i is often seen, representing a major clinical challenge to their widespread use. Investigations to understand mechanisms of resistance to CDK4/6i will contribute to the better use of current CDK4/6i through identification of biomarkers to response and for development of additional therapeutic strategies following progression on CDK4/6i.
Towards understanding CDK4/6i resistance, I have investigated potential resistance mechanisms through the generation of resistance models in ER+ cell lines. I have adapted the Synergistic activating mediator (SAM) and inducible dihydrofolate reductase (DHFR) systems to singly over-express cyclins and CDKs to determine if upregulation of alternative cell cycle CDKs can promote evasion of CDK4/6- directed growth inhibition. Altogether, I have shown that over-expression CDK2 and CDK6 in MCF7 cells leads to rapid emergence of resistance to CDK4/6i...