Pharmacological Inhibition of the Protein Kinase MRK/ZAK Radiosensitizes Medulloblastoma

Daniel Markowitz, Caitlin Powell, Nhan L. Tran, Michael E. Berens, Timothy C. Ryken, Magimairajan Vanan, Lisa Rosen, Mingzu He, Shan Sun, Marc Symons, Yousef Al-Abed, Rosamaria Ruggieri

Research output: Contribution to journalArticle

4 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)1799-1808
Number of pages10
JournalMolecular cancer therapeutics
Volume15
Issue number8
DOIs
StatePublished - Aug 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Markowitz, D., Powell, C., Tran, N. L., Berens, M. E., Ryken, T. C., Vanan, M., Rosen, L., He, M., Sun, S., Symons, M., Al-Abed, Y., & Ruggieri, R. (2016). Pharmacological Inhibition of the Protein Kinase MRK/ZAK Radiosensitizes Medulloblastoma. Molecular cancer therapeutics, 15(8), 1799-1808. https://doi.org/10.1158/1535-7163.MCT-15-0849