Abstract 4915: High degree of G2/M arrest induced by Polo-like kinase 1 (PLK1) inhibition is associated with radiosensitization

Abstract

Abstract Inhibition of polo-like kinase 1 (PLK1) seems to be a plausible avenue for sensitizing cancer cells to radiation. It has been demonstrated that normal cells tolerate PLK1 depletion well, when compared to cancer cells, suggesting a wide therapeutic index. This has been confirmed with our results from proliferation assays conducted with two primary human cell lines and various cancer cell lines. Recently, it has been shown that head-and-neck squamous cell carcinoma and medulloblastoma cells can be radiosensitized by PLK1 inhibition. Furthermore, PLK1 is involved in repair of DNA double-strand breaks. Together, these results suggest that PLK1 inhibition is a particularly attractive means of radiosensitization. To further investigate the radiosensitization property of PLK1 inhibition, clonogenic assays were carried out. Various cancer cell lines were treated with specific PLK1 inhibitor BI 2536 and subjected to various doses of ionizing radiation. The cancer cell lines were of breast, colorectal, and pancreatic origin. We found that some, but not all, cancer cells were radiosensitized by pre-treatment with BI 2536. Mutational statuses of p53 and KRAS were examined, but no relationship between the mutational statuses and radiosensitization by BI 2536 treatment was found. Since PLK1 inhibition causes G2/M arrest, which is the cell cycle phase that is known to be more sensitive to ionizing radiation, we assessed the percentage of cancer cells at G2/M phase when treated with or without BI 2536. Cells were treated with BI 2536 for 24 hrs before they were fixed, stained with propidium iodide, and analyzed with flow cytometry. The degree of G2/M arrest induction was assessed by G2/M induction index, as defined by % of G2/M cells before treatment / % of G2/M cells after treatment. We found that the G2/M induction indices were significantly higher with the cells that can be radiosensitized with PLK1 inhibition, when compared to those of the cells that cannot be radiosensitized. Therefore, we conclude that high G2/M induction index is predictive of radiosensitization with PLK1 inhibition. Future experiments of this project include determining the G2/M induction index threshold required for achieving radiosensitization and indentifying the molecular basis of such association. Citation Format: Nelson Wong, Mohamed Khan. High degree of G2/M arrest induced by Polo-like kinase 1 (PLK1) inhibition is associated with radiosensitization. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4915. doi:10.1158/1538-7445.AM2014-4915