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

Antonio Giordano,Maya Ridinger,Christiana Kappler,Yeonhee Park,Carolyn Britten,Stephen Ethier,Kent Armeson,James Reuben,Yueying Liu,Elizabeth Yeh,Mark Erlander

doi:10.1371/journal.pone.0224420

Abstract

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.

Highlights

According to the synergistic combination of docetaxel and cisplatin with GSK461364 we have observed in SUM149 and SUM159 cells, we focused on these two cell lines in the experiments. (C), Colony forming assay photographs for single agents GSK461364, docetaxel, and cisplatin, with the respective combinations, in SUM149 and SUM159. (D) Histograms show colony formation rates, normalized to DMSO colony number for each cell line, for single drug and respective combinations; GSK461364 plus docetaxel interacted synergistically to decrease the clonogenic potential of SUM149 and SUM159 (p < 0.001 and p < 0.001, respectively; Interaction Test, p = 0.001 and p = 0.03+, respectively)
In our study we showed that polo-like kinase 1 (Plk1) inhibition synergizes with taxane and cisplatin in SUM149, and in SUM159 cells, two subtypes of Triple-negative breast cancer (TNBC) known to have poor response to conventional chemotherapy [59]
Based on the fact that Plk1 is required for mitotic entry during recovery from G2 arrest induced by DNA damage [60], and based on our preliminary data in which Plk1 is a functional key gene in the basal-like cell line SUM149, we demonstrated that Plk1 inhibition synergized with chemotherapies such as taxane, inhibiting the G2-M transition, inducing aberrant mitotic exit, and apoptosis and the elimination of stem cell-like resistant tumor clones