Browsing by Author "Armeson, Kent"

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    Correction: HUNK phosphorylates EGFR to regulate breast cancer metastasis
    (Springer Nature, 2021-05) Williams, Carly B.; Phelps-Polirer, Kendall; Dingle, Ivan P.; Williams, Christina J.; Rhett, Matthew J.; Eblen, Scott T.; Armeson, Kent; Hill, Elizabeth G.; Yeh, Elizabeth S.; Pharmacology and Toxicology, School of Medicine
    Erratum for 10.1038/s41388-019-1046-5
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    HUNK phosphorylates EGFR to regulate breast cancer metastasis
    (Springer Nature, 2019-10-09) Williams, Carly B.; Phelps-Polirer, Kendall; Dingle, Ivan P.; Williams, Christina J.; Rhett, Matthew J.; Eblen, Scott T.; Armeson, Kent; Hill, Elizabeth G.; Yeh, Elizabeth S.; Pharmacology and Toxicology, School of Medicine
    Epidermal growth factor receptor (EGFR) is commonly over-expressed in metastatic breast cancer yet metastatic breast cancer is generally resistant to anti-EGFR therapies, and the mechanism for resistance to EGFR inhibitors in this setting is not fully understood. Hormonally up-regulated neu-associated kinase (HUNK) kinase is up-regulated in aggressive breast cancers and is thought to play a role in breast cancer metastasis. However, no studies have been conducted to examine a relationship between EGFR and HUNK in breast cancer metastasis. We performed a kinase substrate screen and identified that EGFR is phosphorylated by HUNK. Our studies show that HUNK phosphorylates EGFR at T654, enhancing receptor stability and downstream signaling. We found that increased phosphorylation of T654 EGFR correlates with increased epithelial to mesenchymal, migration and invasion, and metastasis. In addition, we found that HUNK expression correlates with overall survival and distant metastasis free survival. This study shows that HUNK directly phosphorylates EGFR at T654 to promote metastasis and is the first study to show that the phosphorylation of this site in EGFR regulates metastasis.
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    Polo-like kinase 1 (Plk1) inhibition synergizes with taxanes in triple negative breast cancer
    (Public Library of Science, 2019-11-21) Giordano, Antonio; Liu, Yueying; Armeson, Kent; Park, Yeonhee; Ridinger, Maya; Erlander, Mark; Reuben, James; Britten, Carolyn; Kappler, Christiana; Yeh, Elizabeth; Ethier, Stephen; Pathology and Laboratory Medicine, School of Medicine
    Within triple negative breast cancer, several molecular subtypes have been identified, underlying the heterogeneity of such an aggressive disease. The basal-like subtype is characterized by mutations in the TP53 gene, and is associated with a low pathologic complete response rate following neoadjuvant chemotherapy. In a genome-scale short hairpin RNA (shRNA) screen of breast cancer cells, polo-like kinase 1 (Plk1) was a frequent and strong hit in the basal breast cancer cell lines indicating its importance for growth and survival of these breast cancer cells. Plk1 regulates progression of cells through the G2-M phase of the cell cycle. We assessed the activity of two ATP-competitive Plk1 inhibitors, GSK461364 and onvansertib, alone and with a taxane in a set of triple negative breast cancer cell lines and in vivo. GSK461364 showed synergism with docetaxel in SUM149 (Combination Index 0.70) and SUM159 (CI, 0.62). GSK461364 in combination with docetaxel decreased the clonogenic potential (interaction test for SUM149 and SUM159, p<0.001 and p = 0.01, respectively) and the tumorsphere formation of SUM149 and SUM159 (interaction test, p = 0.01 and p< 0.001). In the SUM159 xenograft model, onvansertib plus paclitaxel significantly decreased tumor volume compared to single agent paclitaxel (p<0.0001). Inhibition of Plk1 in combination with taxanes shows promising results in a subset of triple negative breast cancer intrinsically resistant to chemotherapy. Onvansertib showed significant tumor volume shrinkage when combined with paclitaxel in vivo and should be considered in clinical trials for the treatment of triple negative cancers.