Graduation Date

Summer 8-11-2023

Document Type

Thesis

Degree Name

Master of Science (MS)

Programs

Cancer Research

First Advisor

Amar Natarajan

Second Advisor

Dalia El-Gamal

Third Advisor

Grinu Mathew

Abstract

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.

Comments

2023 Copyright, the authors

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