Date of Award

Spring 2021

Degree Type

Thesis

Department

College of Pharmacy

Director of Thesis

Eugenia Broude, PhD

First Reader

Zachary Mack

Second Reader

Zachary Mack

Abstract

Cyclin-dependent kinases (CDK) 4 and 6 are the main drivers of proliferation in estrogen receptor (ER)-positive breast cancer cells. CDK4/6 inhibitors, such as the FDA-approved cytostatic drug, Palbociclib, induce G1 arrest and prevent cell cycle progression. Prolonged treatment with CDK4/6 inhibitors can lead to drug resistance in the clinic as well as in the lab. The mechanisms behind this resistance are varied, with preliminary evidence suggesting that it may be influenced by the senescence-associated secretory phenotype (SASP), CDK6 hyperactivation, or degradation of the retinoblastoma protein (Rb). In contrast to the cell cycle mediating CDK4/6, CDK8 and 19 are involved in regulating transcription. CDK8/19 phosphorylate the C-terminal domain (CTD) of RNA polymerase II (Pol II), inducing the elongation of transcription. Studies have shown that high CDK8/19 expression is associated with shorter relapse-free survival and failure of systemic therapy in breast cancer. Preliminary data suggest the inhibition of CDK8/19 successfully prevents resistance to CDK4/6 inhibitors, resulting in complete elimination of cancer cells. This project will help establish why combination therapy with CDK8/19 inhibitors prevents drug resistance to CDK4/6 inhibitors via the suppression of ER-regulated transcription of mitogenic factors. This drug combination therapy may have clinical relevance for preventing drug resistance in ER-positive breast cancer.

First Page

1

Last Page

15

Rights

© 2021, Samantha Tolentino Safa

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