Master of Science (MS)
Hormone receptor-positive (HR+) breast cancer (BC) constitutes approximately 75% of all breast cancer patients. These tumors rely on hormones, estrogen and progesterone, for their proliferation. The interaction between the hormones and their respective receptors enhances cyclin D expression, which results in the persistent activation of CDK4 and CDK6. The CDK4/6-cyclin D complex engages in a phosphorylation cascade that ultimately allows the cells to proceed past the G1/S checkpoint of the cell cycle. Inhibition of CDK4/6 has been shown to trigger cell cycle arrest, inhibit tumor growth, and induce apoptosis. Currently, there are three FDA-approved CDK4/6 inhibitors (CDK4/6i). A limitation of prolonged treatment with CDK4/6i is drug resistance. One mechanism for the acquired resistance toward CDK4/6i is the overexpression of CDK6. The aim of this project is to utilize a CDK6-selective PROTAC to reduce the levels of CDK4/6i-induced overexpressed CDK6 proteins in CDK4/6i-resistant BC cell lines. To study the central question, T47D, an HR+ breast cancer cell line, was established to be resistant towards each of the three CDK4/6i: Palbociclib, Ribociclib, and Abemaciclib. Resistance to CDK4/6i in these cell lines was assessed via growth inhibition studies and cell cycle analyses. Combined treatment of CDK4/6i with the CDK6-selective PROTAC synergistically inhibits the growth of CDK4/6i-resistant HR+ breast cancer cells. The observed synergism highlights the possibility of employing a PROTAC with the kinase inhibitors to overcome resistance. This data may aid in the design of novel therapeutic strategies to improve overall patient outcomes.
Truong, Sarah, "Overcoming Resistance Mechanisms to CDK4/6 Inhibitor Treatment Using CDK6-Selective PROTAC" (2023). Theses & Dissertations. 752.
Available for download on Thursday, June 26, 2025