Oncometabolite D-2-Hydroxyglutarate Inhibits ALKBH DNA Repair Enzymes and Sensitizes IDH Mutant Cells to Alkylating Agents

• Published in: Cell reports (Cambridge) Vol. 13; no. 11; pp. 2353 - 2361
• Main Authors: Wang, Pu, Wu, Jing, Ma, Shenghong, Zhang, Lei, Yao, Jun, Hoadley, Katherine A., Wilkerson, Matthew D., Perou, Charles M., Guan, Kun-Liang, Ye, Dan, Xiong, Yue
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.12.2015; Elsevier
• Subjects: AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase; Alkylating Agents - toxicity; Busulfan - toxicity; Cell Line, Tumor; Dioxygenases - antagonists & inhibitors; Dioxygenases - genetics; Dioxygenases - metabolism; DNA Damage - drug effects; DNA Repair - drug effects; DNA Repair Enzymes - antagonists & inhibitors; DNA Repair Enzymes - genetics; DNA Repair Enzymes - metabolism; Glutarates - metabolism; Glutarates - pharmacology; Humans; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - metabolism; Ketoglutaric Acids - metabolism; Mutation; Protein Binding; RNA Interference; RNA, Small Interfering - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2015.11.029

Chemotherapy of a combination of DNA alkylating agents, procarbazine and lomustine (CCNU), and a microtubule poison, vincristine, offers a significant benefit to a subset of glioma patients. The benefit of this regimen, known as PCV, was recently linked to IDH mutation that occurs frequently in glioma and produces D-2-hydroxyglutarate (D-2-HG), a competitive inhibitor of α-ketoglutarate (α-KG). We report here that D-2-HG inhibits the α-KG-dependent alkB homolog (ALKBH) DNA repair enzymes. Cells expressing mutant IDH display reduced repair kinetics, accumulate more DNA damages, and are sensitized to alkylating agents. The observed sensitization to alkylating agents requires the catalytic activity of mutant IDH to produce D-2-HG and can be reversed by the deletion of mutant IDH allele or overexpression of ALKBH2 or AKLBH3. Our results suggest that impairment of DNA repair may contribute to tumorigenesis driven by IDH mutations and that alkylating agents may merit exploration for treating IDH-mutated cancer patients. [Display omitted] •IDH mutations and 2HG inhibit the DNA repair enzyme ALKBH•IDH mutant cells are sensitized to alkylating agents•Alkylating chemotherapy agents should be explored for treating IDH-mutated tumors Wang et al. demonstrate that D-2-HG produced by mutant IDH inhibits alkylated DNA repair enzymes, leading to DNA damage and sensitizing IDH mutant cells to alkylating agents. These results suggest that impairment of DNA repair may contribute to tumorigenesis driven by IDH mutations and that alkylating agents should be explored as a therapeutic option for IDH-mutated cancer patients.