ATM regulates 3-methylpurine-DNA glycosylase and promotes therapeutic resistance to alkylating agents.

Abstract

UNLABELLED:

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.

• Authors: Sameer Agnihotri, Kelly Burrell, Pawel Buczkowicz, Marc Remke, Brian Golbourn, Yevgen Chornenkyy, Aaron Gajadhar, Nestor A Fernandez, Ian D Clarke, Mark S Barszczyk, Sanja Pajovic, Christian Ternamian, Renee Head, Nesrin Sabha, Robert W Sobol, Michael D Taylor, James T Rutka, Chris Jones, Peter B Dirks, Gelareh Zadeh, Cynthia Hawkins
• Journal: Cancer discovery (Cancer Discov) Vol. 4 Issue 10 Pg. 1198-213 (Oct 2014) ISSN: 2159-8290 [Electronic] United States
• PMID: 25100205 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents, Alkylating
• RNA, Small Interfering
• Dacarbazine
• Ataxia Telangiectasia Mutated Proteins
• DNA Glycosylases
• Temozolomide

Topics

• Age Factors
• Animals
• Antineoplastic Agents, Alkylating (pharmacology)
• Ataxia Telangiectasia Mutated Proteins (metabolism)
• Cell Line, Tumor
• Cluster Analysis
• DNA Copy Number Variations
• DNA Glycosylases (metabolism)
• DNA Repair
• Dacarbazine (analogs & derivatives, pharmacology)
• Disease Models, Animal
• Drug Resistance, Neoplasm (genetics)
• Enzyme Activation
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Glioblastoma (drug therapy, genetics, metabolism, mortality, pathology)
• Humans
• Models, Biological
• Phosphorylation
• RNA Interference
• RNA, Small Interfering (genetics)
• Temozolomide
• Xenograft Model Antitumor Assays