Work

MK-8776, a novel chk1 kinase inhibitor, radiosensitizes p53-defective human tumor cells

Year: 2016

Type: article

Abstract: // Kathleen A. Bridges 1 , Xingxing Chen 1, 4 , Huifeng Liu 1 , Crosby Rock 1 , Thomas A. Buchholz 2 , Stuart D. Shumway 3 , Heath D. Skinner 2 , Raymond E. Meyn 1 1 Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Merck Research Laboratories, Boston, MA, USA 4 Present address: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China Correspondence to: Raymond E. Meyn, email: [email protected] Keywords: radiation, Chk1, p53-dependent, MK-8776, DNA damage Received: July 20, 2016 Accepted: September 20, 2016 Published: September 28, 2016 ABSTRACT Radiotherapy is commonly used to treat a variety of solid tumors but improvements in the therapeutic ratio are sorely needed. The aim of this study was to assess the Chk1 kinase inhibitor, MK-8776, for its ability to radiosensitize human tumor cells. Cells derived from NSCLC and HNSCC cancers were tested for radiosensitization by MK-8776. The ability of MK-8776 to abrogate the radiation-induced G2 block was determined using flow cytometry. Effects on repair of radiation-induced DNA double strand breaks (DSBs) were determined on the basis of rad51, γ-H2AX and 53BP1 foci. Clonogenic survival analyses indicated that MK-8776 radiosensitized p53-defective tumor cells but not lines with wild-type p53. Abrogation of the G2 block was evident in both p53-defective cells and p53 wild-type lines indicating no correlation with radiosensitization. However, only p53-defective cells entered mitosis harboring unrepaired DSBs. MK-8776 appeared to inhibit repair of radiation-induced DSBs at early times after irradiation. A comparison of MK-8776 to the wee1 inhibitor, MK-1775, suggested both similarities and differences in their activities. In conclusion, MK-8776 radiosensitizes tumor cells by mechanisms that include abrogation of the G2 block and inhibition of DSB repair. Our findings support the clinical evaluation of MK-8776 in combination with radiation.

Source: Oncotarget

DOI: 10.18632/oncotarget.12311