Finding Synergistic Lipid Kinase and Mitotic Kinase Inhibitor Combination Treatments for Metastatic Breast Cancer
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Authors
Al Ali, Nadia
Date
2024-01-17
Type
thesis
Language
eng
Keyword
Triple negative breast cancer , Inflammatory breast cancer , PI3K pathway , AURKA pathway , Alisertib , Buparlisib
Alternative Title
Abstract
Triple-negative breast cancer (TNBC) and Inflammatory breast cancer (IBC) are aggressive subtypes that lack targeted therapies options in most cases. The frequently activated phosphatidylinositol 3 kinase (PI3K) pathway in TNBC is a candidate but resistance to PI3K inhibitors has been observed. However, a recent functional genomics screen using PI3K inhibitor buparlisib in TNBC cells revealed a synthetic lethal interaction with Aurora kinase A (AURKA) gene. Here, I investigated if PI3K and AURKA inhibitors will act synergistically to eliminate TNBC cell growth and motility in culture models and halt progression in mouse tumor models. Testing dose responses of buparlisib and/or alisertib treatments in TNBC and IBC cell lines revealed synergistic effects that increased cytotoxicity in a dose dependent fashion by up to 10-fold change. The combination of buparlisib and alisertib were also better than monotherapies at reducing TNBC or IBC colony growth and cell migration rates. Combination treatments of IBC tumor-bearing mice with buparlisib and alisertib also reduced tumor growth and spontaneous lung metastases in vivo. Together, these results provide rationale for advancing targeted therapies comprised of PI3K and AURKA inhibitors to improve treatment options for TNBC and IBC.
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Attribution-NonCommercial-NoDerivatives 4.0 International
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
Attribution-NonCommercial-NoDerivatives 4.0 International