Finding Synergistic Lipid Kinase and Mitotic Kinase Inhibitor Combination Treatments for Metastatic Breast Cancer

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Al Ali, Nadia
Triple negative breast cancer , Inflammatory breast cancer , PI3K pathway , AURKA pathway , Alisertib , Buparlisib
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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