title: Pharmacological Inhibition of the Protein Kinase MRK/ZAK Radiosensitizes Medulloblastoma.
abstract: Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiotherapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain. We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell-cycle arrest after ionizing radiation. Here, we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a specific small molecule inhibitor of MRK, M443, which binds to MRK in an irreversible fashion and inhibits its activity. We found that M443 strongly radiosensitizes UW228 medulloblastoma cells as well as UI226 patient-derived primary cells, whereas it does not affect the response to radiation of normal brain cells. M443 also inhibits radiation-induced activation of both p38 and Chk2, two proteins that act downstream of MRK and are involved in DNA damage-induced cell-cycle arrest. Importantly, in an animal model of medulloblastoma that employs orthotopic implantation of primary patient-derived UI226 cells in nude mice, M443 in combination with radiation achieved a synergistic increase in survival. We hypothesize that combining radiotherapy with M443 will allow us to lower the radiation dose while maintaining therapeutic efficacy, thereby minimizing radiation-induced side effects. Mol Cancer Ther; 15(8); 1799-808. ©2016 AACR.
authors.affiliation: Center of Oncology and Cell Biology, Feinstein Institute, Manhasset, New York.
authors.forename: Daniel
authors.initials: D
authors.lastname: Markowitz
authors.affiliation: Center of Oncology and Cell Biology, Feinstein Institute, Manhasset, New York.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Powell
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: Nhan L
authors.initials: NL
authors.lastname: Tran
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Berens
authors.affiliation: Department of Neurosurgery, Kansas University Medical Center, Kansas City, Kansas.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Ryken
authors.affiliation: Section of Pediatric Hematology/Oncology/BMT, University of Manitoba, Winnipeg, Canada.
authors.forename: Magimairajan
authors.initials: M
authors.lastname: Vanan
authors.affiliation: Biostatistic Unit, Feinstein Institute, Manhasset, New York.
authors.forename: Lisa
authors.initials: L
authors.lastname: Rosen
authors.affiliation: Center for Molecular Innovation, Feinstein Institute, Manhasset, New York.
authors.forename: Mingzu
authors.initials: M
authors.lastname: He
authors.affiliation: Center for Molecular Innovation, Feinstein Institute, Manhasset, New York.
authors.forename: Shan
authors.initials: S
authors.lastname: Sun
authors.affiliation: Center of Oncology and Cell Biology, Feinstein Institute, Manhasset, New York. mruggier@northwell.edu msymons@northwell.edu.
authors.forename: Marc
authors.initials: M
authors.lastname: Symons
authors.affiliation: Center for Molecular Innovation, Feinstein Institute, Manhasset, New York.
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
authors.affiliation: Center of Oncology and Cell Biology, Feinstein Institute, Manhasset, New York. mruggier@northwell.edu msymons@northwell.edu.
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Ruggieri
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002528:Cerebellar Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D004249:DNA Damage; D004195:Disease Models, Animal; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D020930:MAP Kinase Kinase Kinases; D008527:Medulloblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D011838:Radiation-Sensitizing Agents; D011494:Protein Kinases; D020930:MAP Kinase Kinase Kinases; C413047:MAP3K20 protein, human