TY - JOUR
T1 - Pharmacological Inhibition of the Protein Kinase MRK/ZAK Radiosensitizes Medulloblastoma
AU - Markowitz, Daniel
AU - Powell, Caitlin
AU - Tran, Nhan L.
AU - Berens, Michael E.
AU - Ryken, Timothy C.
AU - Vanan, Magimairajan
AU - Rosen, Lisa
AU - He, Mingzu
AU - Sun, Shan
AU - Symons, Marc
AU - Al-Abed, Yousef
AU - Ruggieri, Rosamaria
N1 - Publisher Copyright:
© 2016 AACR.
PY - 2016/8
Y1 - 2016/8
N2 - 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 medulloblastomacellsaswellasUI226patient-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.
AB - 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 medulloblastomacellsaswellasUI226patient-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.
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U2 - 10.1158/1535-7163.MCT-15-0849
DO - 10.1158/1535-7163.MCT-15-0849
M3 - Article
C2 - 27207779
AN - SCOPUS:84985993336
SN - 1535-7163
VL - 15
SP - 1799
EP - 1808
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 8
ER -