The Role of Spy1 in CDK4/6 Inhibitor Resistance in Estrogen-receptor Positive Breast Cancer

Estrogen-receptor positive (ER+) breast cancer is the most common breast cancer subtype, accounting for 70% of breast cancer diagnoses. The standard of care treatment for ER+ breast cancer is endocrine therapy, however 30-50% of patients develop resistance. Palbociclib is a cyclin-dependent kinase (CDK) 4/6 inhibitor that works synergistically with endocrine therapy, yet patients can acquire CDK4/6 inhibitor resistance. Underlying mechanisms in acquiring CDK4/6 inhibitor resistance are still being explored, with data supporting CDK2/Cyclin E hyperactivation as a key driver of resistance. Spy1 (Speedy/RINGO), a cyclin-like protein, promotes cell cycle progression through the G1/S checkpoint. Spy1 directly binds and activates CDK2, irrespective of post-translational modifications required for canonical cyclin-CDK activation. The unique Spy1-CDK2 complex is resistant to p21 and p27 inhibition, thus promoting cell cycle progression. Previous data shows that elevated Spy1 promotes treatment resistance in ER+ breast cancer. Given the unique ability of Spy1 to hyperactivate CDK2 through Spy1-CDK2 complex formation, Spy1-CDK2 activation may give rise to CDK4/6 inhibitor resistance in ER+ breast cancer. This project aims to investigate the role of Spy1 in CDK4/6 inhibitor resistance using the Casper zebrafish model and evaluate the manipulation of Spy1 on the cellular response to palbociclib in ER+ breast cancer.