Date of Award

Spring 2022

Degree Type

Thesis

Department

College of Pharmacy

Director of Thesis

Dr. Eugenia Broude

Second Reader

Zachary Mack

Abstract

Breast cancer remains the highest cause of worldwide cancer-related mortality. Unfortunately, acquired therapeutic resistance occurs in the majority of cases of estrogen receptor-positive breast cancer. An effort to discover drugs which act synergistically with Palbociclib and prevent the development of resistance and tumor growth is essential to improving patient outcomes. Cyclin dependent kinases (CDK) 8 and 19 are Mediator complex proteins. The Mediator complex is an enzymatic module regulating transcription. The goal of the research is to elucidate the mechanism by which CDK8/19 inhibitor, SNX631, prevents acquired resistance to CDK4/6 inhibitor, Palbociclib. The present study aims to elucidate the role of the senescence-associated secretory phenotype (SASP) in Palbociclib resistance, and furthermore, to investigate if SASP is mitigated by a novel CDK8/19 inhibitor, SNX631. It was determined that SASP was suppressed by Palbociclib and therefore not a contributor to resistance. TGF-B, a member of SASP, was identified as a key modulator of both tumorigenesis and cell cycle arrest in breast cancer. The possibility that SNX631 suppresses TGF-B signaling to prevent Palbociclib resistance was explored. Overall, it was determined that SNX631 suppresses TGF-B/Smad3 signaling preventing changes to TGF-B signaling that occur throughout Palbociclib treatment. Lastly, alternative mechanisms of Palbociclib resistance are present, and they should be further explored in the context of SNX631.

First Page

1

Last Page

36

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