Polo-like kinase 1 (Plk1) inhibition synergizes with taxanes in triple negative breast cancer


Autoři: Antonio Giordano aff001;  Yueying Liu aff001;  Kent Armeson aff002;  Yeonhee Park aff002;  Maya Ridinger aff003;  Mark Erlander aff003;  James Reuben aff004;  Carolyn Britten aff001;  Christiana Kappler aff005;  Elizabeth Yeh aff006;  Stephen Ethier aff005
Působiště autorů: Department of Medicine, Division of Hematology & Oncology, Medical University of South Carolina, Charleston, South Carolina, United States of America aff001;  Department of Public Health Sciences, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, United States of America aff002;  Trovagene Oncology, San Diego, California, United States of America aff003;  Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America aff004;  Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America aff005;  Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indianapolis, United States of America aff006
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224420

Souhrn

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.

Klíčová slova:

Apoptosis – Breast cancer – Cancer chemotherapy – Cancer treatment – Cell cycle and cell division – Drug therapy – Chemotherapy – Phase I clinical investigation


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