title: ATM regulates 3-methylpurine-DNA glycosylase and promotes therapeutic resistance to alkylating agents.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Sameer
authors.initials: S
authors.lastname: Agnihotri
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Kelly
authors.initials: K
authors.lastname: Burrell
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Pawel
authors.initials: P
authors.lastname: Buczkowicz
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Golbourn
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Yevgen
authors.initials: Y
authors.lastname: Chornenkyy
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Aaron
authors.initials: A
authors.lastname: Gajadhar
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Nestor A
authors.initials: NA
authors.lastname: Fernandez
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Clarke
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Barszczyk
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Sanja
authors.initials: S
authors.lastname: Pajovic
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Ternamian
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Renee
authors.initials: R
authors.lastname: Head
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Nesrin
authors.initials: N
authors.lastname: Sabha
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, Pennsylvania. Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sobol
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: James T
authors.initials: JT
authors.lastname: Rutka
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dirks
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada. Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Canada.
authors.forename: Gelareh
authors.initials: G
authors.lastname: Zadeh
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada. Division of Pathology, The Hospital for Sick Children, University of Toronto, Toronto, Canada. cynthia.hawkins@sickkids.ca.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hawkins
mesh_terms: D000367:Age Factors; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D056915:DNA Copy Number Variations; D045647:DNA Glycosylases / Q000378:metabolism*; D004260:DNA Repair; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D006801:Humans; D008954:Models, Biological; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D034741:RNA, Small Interfering; D003606:Dacarbazine; D064007:Ataxia Telangiectasia Mutated Proteins; D045647:DNA Glycosylases; D000077204:Temozolomide
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