MK-8776, a novel chk1 kinase inhibitor, radiosensitizes p53-defective human tumor cells
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Kathleen A. Bridges1, Xingxing Chen1,4, Huifeng Liu1, Crosby Rock1, Thomas A. Buchholz2, Stuart D. Shumway3, Heath D. Skinner2, Raymond E. Meyn1
1Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3Merck Research Laboratories, Boston, MA, USA
4Present address: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
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
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.
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