title: MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells.
abstract: OBJECTIVE
  Radiotherapy is commonly used to treat a variety of solid tumors. However, improvements in the therapeutic ratio for several disease sites are sorely needed, leading us to assess molecularly targeted therapeutics as radiosensitizers. The aim of this study was to assess the wee1 kinase inhibitor, MK-1775, for its ability to radiosensitize human tumor cells.
  
  
  METHODS
  Human tumor cells derived from lung, breast, and prostate cancers were tested for radiosensitization by MK-1775 using clonogenic survival assays. Both p53 wild-type and p53-defective lines were included. The ability of MK-1775 to abrogate the radiation-induced G₂ block, thereby allowing cells harboring DNA lesions to prematurely progress into mitosis, was determined using flow cytometry and detection of γ-H2AX foci. The in vivo efficacy of the combination of MK-1775 and radiation was assessed by tumor growth delay experiments using a human lung cancer cell line growing as a xenograft tumor in nude mice.
  
  
  RESULTS
  Clonogenic survival analyses indicated that nanomolar concentrations of MK-1775 radiosensitized p53-defective human lung, breast, and prostate cancer cells but not similar lines with wild-type p53. Consistent with its ability to radiosensitize, MK-1775 abrogated the radiation-induced G₂ block in p53-defective cells but not in p53 wild-type lines. MK-1775 also significantly enhanced the antitumor efficacy of radiation in vivo as shown in tumor growth delay studies, again for p53-defective tumors.
  
  
  CONCLUSIONS
  These results indicate that p53-defective human tumor cells are significantly radiosensitized by the potent and selective wee1 kinase inhibitor, MK-1775, in both the in vitro and in vivo settings. Taken together, our findings strongly support the clinical evaluation of MK-1775 in combination with radiation.
authors.affiliation: Department of Experimental Radiation Oncology and Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Bridges
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hirai
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Buser
authors.forename: Colin
authors.initials: C
authors.lastname: Brooks
authors.forename: Huifeng
authors.initials: H
authors.lastname: Liu
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Buchholz
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Molkentine
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Mason
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Meyn
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011744:Pyrimidinones; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C549567:adavosertib