Defense Date

4-23-2019

Graduation Date

Summer 8-10-2019

Availability

One-year Embargo

Submission Type

dissertation

Degree Name

PhD

Department

Pharmacology

School

School of Pharmacy

Committee Chair

Jane E. Cavanaugh

Committee Member

Wilson S. Meng

Committee Member

Lauren O’Donnell

Committee Member

Patrick T. Flaherty

Committee Member

Paula A. Witt-Enderby

Committee Member

David A. Johnson

Keywords

PI3K/Akt, MEK5/ERK5, Synergy, Triple-negative breast cancer

Abstract

Breast cancer is a heterogeneous disease state with several challenging frontiers. In particular, aberrations in the Phosphoinositide-3-kinase (PI3K) and Mitogen Activated Protein Kinase (MAPK) pathways have been linked to increased breast cancer proliferation and survival. It has been proposed that these survival characteristics are enhanced through compensatory signaling and crosstalk mechanisms. New evidence suggests that MEK5/ERK5, a member of the MAPK family, is a crucial component in the proliferation and survival of several aggressive cancers. We hypothesize that inhibiting both PI3K/Akt and MEK5/ERK5 pathways will decrease cell viability while maintaining limited collateral toxicity. In this study, we examined the effects of dual inhibition of PI3K/Akt and MEK5/ERK5 in a panel of hormonally diverse cell lines. Additionally, we investigated dual inhibition in triple-negative breast cancer (TNBC) and tamoxifen resistant models. Both of which do not currently have targeted therapy available. Our results (in TNBC cells) indicate that the dual inhibition strategy was more effective than single inhibition due to the loss of crosstalk between the two pathways. In summary, the results from this study provide a unique perspective into the utility of a novel dual inhibition strategy for targeting TNBCs.

Language

United States

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