MK-8776, a novel chk1 kinase inhibitor, radiosensitizes p53-defective human tumor cells.
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.
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Kathleen A
KA
Bridges
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Present address: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
Xingxing
X
Chen
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Huifeng
H
Liu
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Crosby
C
Rock
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Thomas A
TA
Buchholz
Merck Research Laboratories, Boston, MA, USA.
Stuart D
SD
Shumway
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Heath D
HD
Skinner
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Raymond E
RE
Meyn
D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors*; D053903:DNA Breaks, Double-Stranded; D016195:G2 Phase / Q000528:radiation effects; D006657:Histones / Q000032:analysis; D006801:Humans; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011744:Pyrimidinones; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
C468783:H2AX protein, human; D006657:Histones; C559815:MK-8776; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D011838:Radiation-Sensitizing Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000071877:Checkpoint Kinase 1; C549567:adavosertib
Chk1; DNA damage; MK-8776; p53-dependent; radiation
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