Agnihotri, S., Burrell, K., Buczkowicz, P., Remke, M., Golbourn, B., Chornenkyy, Y., Gajadhar, A., Fernandez, N. A., Clarke, I. D., Barszczyk, M. S., Pajovic, S., Ternamian, C., Head, R., Sabha, N., Sobol, R. W., Taylor, M. D., Rutka, J. T., Jones, C., Dirks, P. B., Zadeh, G., Hawkins, C. (2014) ATM Regulates 3-Methylpurine-DNA Glycosylase and Promotes Therapeutic Resistance to Alkylating Agents. Cancer Discovery, 4 (10). pp. 1198-1213. ISSN 2159-8274

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Abstract

Alkylating agents are a first-line therapy for the treatment of several aggressive cancers, including pediatric glioblastoma, a lethal tumor in children. Unfortunately, many tumors are resistant to this therapy. We sought to identify ways of sensitizing tumor cells to alkylating agents while leaving normal cells unharmed, increasing therapeutic response while minimizing toxicity. Using an siRNA screen targeting over 240 DNA damage response genes, we identified novel sensitizers to alkylating agents. In particular, the base excision repair (BER) pathway, including 3-methylpurine-DNA glycosylase (MPG), as well as ataxia telangiectasia mutated (ATM), were identified in our screen. Interestingly, we identified MPG as a direct novel substrate of ATM. ATM-mediated phosphorylation of MPG was required for enhanced MPG function. Importantly, combined inhibition or loss of MPG and ATM resulted in increased alkylating agent-induced cytotoxicity in vitro and prolonged survival in vivo. The discovery of the ATM-MPG axis will lead to improved treatment of alkylating agent-resistant tumors. SIGNIFICANCE: Inhibition of ATM and MPG-mediated BER cooperate to sensitize tumor cells to alkylating agents, impairing tumor growth in vitro and in vivo with no toxicity to normal cells, providing an ideal therapeutic window. (C) 2014 AACR.

Item Type:	Article
Authors (ICR Faculty only):	Jones, Chris
All Authors:	Agnihotri, S., Burrell, K., Buczkowicz, P., Remke, M., Golbourn, B., Chornenkyy, Y., Gajadhar, A., Fernandez, N. A., Clarke, I. D., Barszczyk, M. S., Pajovic, S., Ternamian, C., Head, R., Sabha, N., Sobol, R. W., Taylor, M. D., Rutka, J. T., Jones, C., Dirks, P. B., Zadeh, G., Hawkins, C.
Additional Information:	ISI Document Delivery No.: AW8GP Times Cited: 1 Cited Reference Count: 53 Agnihotri, Sameer Burrell, Kelly Buczkowicz, Pawel Remke, Marc Golbourn, Brian Chornenkyy, Yevgen Gajadhar, Aaron Fernandez, Nestor A. Clarke, Ian D. Barszczyk, Mark S. Pajovic, Sanja Ternamian, Christian Head, Renee Sabha, Nesrin Sobol, Robert W. Taylor, Michael D. Rutka, James T. Jones, Chris Dirks, Peter B. Zadeh, Gelareh Hawkins, Cynthia Warren Foltz; Spatio-Temporal Targeting and Amplification of Radiation Response (STTARR) program The authors thank Dr. Geoff Margison at the Paterson Institute for Cancer Research for input and evaluation of the article. For MRI images, they thank Dr. Warren Foltz and the Spatio-Temporal Targeting and Amplification of Radiation Response (STTARR) program and its affiliated funding agencies. The MPG-GST construct was a generous gift from Dr. Mitsuyoshi Nakao (Institute of Molecular Embryology and Genetics Kumamoto University). The authors also thank Dr. Michael Kastan for the ATM construct (Duke University School of Medicine). Both the MPG-GST and ATM constructs were obtained by a materials transfer agreement. 1 AMER ASSOC CANCER RESEARCH PHILADELPHIA CANCER DISCOV
Uncontrolled Keywords:	BASE EXCISION-REPAIR DNA-N-GLYCOSYLASE INTRINSIC PONTINE GLIOMAS HIGH-GRADE GLIOMAS GLIOBLASTOMA-MULTIFORME TEMOZOLOMIDE RESISTANCE PEDIATRIC GLIOBLASTOMA CHECKPOINT ACTIVATION MALIGNANT GLIOMAS DRUG TEMOZOLOMIDE Oncology
Research teams:	ICR divisions > Molecular Pathology > Glioma Team
Depositing User:	Users 11 not found.
Date Deposited:	15 Jan 2015 16:17
Last Modified:	15 Jan 2015 16:17
URI:	http://publications.icr.ac.uk/id/eprint/13822

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