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  • The unique property of mutant IDH in producing an oncometabo

    2019-08-13

    The unique property of mutant IDH1/2 in producing an oncometabolite that has no known physiological function makes mutant IDH enzymes as obvious potential therapeutic targets for the treatment of IDH-mutated tumors (Rohle et al., 2013, Wang et al., 2013). Clinical studies have also suggested the presence of a sequela target(s) for treating IDH-mutated gliomas. Following an early study showing successful chemotherapy for recurrent malignant oligodendroglioma (Cairncross and Macdonald, 1988), randomized controlled trials were carried out in both the North America (RTOG 9402) and Europe (EORTC 26951). These studies have shown clear benefits for both anaplastic oligodendroglioma (AO) and oligoastrocytoma (AOA) patients who in addition to radiation therapy received chemotherapy of procarbazine, CCNU/lomustine, and vincristine (PCV) (Cairncross et al., 2013, Cairncross et al., 2014, Erdem-Eraslan et al., 2013, van den Bent et al., 2013). PCV benefit was recently linked to IDH1 mutations with an overall survival of 9.4 years for IDH-mutated patients versus 5.7 years for patients with wild-type IDH (Cairncross et al., 2014). Of three agents in PCV regimen, vincristine inhibits microtubule assembly, and CCNU and procarbazine are DNA alkylating agents. The molecular mechanism(s) underlying the therapeutic benefits that are conferred by PCV is not known and is investigated in this study.
    Results
    Discussion This study provides two insights into the IDH mutation. First, our results suggest a mechanism by which IDH mutation contributes to tumorigenesis. There is strong evidence that IDH1/2 mutations alter epigenetic regulation in affected Sulfaphenazole (Chowdhury et al., 2011, Figueroa et al., 2010, Noushmehr et al., 2010, Sasaki et al., 2012, Xu et al., 2011). We show in this study that in addition to altering epigenetic control, impairment of DNA repair may also contribute to tumorigenesis driven by IDH mutation. Second, the results presented here implicate a targeted therapy for treating patients with IDH1/2-mutated tumors. As demonstrated in this study, glioma cells or chondrosarcoma cells with expression of mutant IDH1 are significantly more sensitive to MNNG, MMS, busulfan, and CCNU, compared to cells expressing only wild-type IDH1, suggesting that the classical alkylating agents may be an appropriate and “targeted” therapy for patients with IDH1/2-mutated cancers. This hypothesis is supported by the results of the aforementioned trials showing that four to six Sulfaphenazole cycles of PCV were sufficient with RT to double the survival of patients with AO and AOA (Cairncross et al., 2013, Erdem-Eraslan et al., 2013, van den Bent et al., 2013). The PCV benefit was recently linked to IDH mutation (Cairncross et al., 2014). Our study provides a molecular basis for the PCV benefit linked to IDH mutation. Our finding that IDH mutation and 2HG accumulation sensitize cells to CCNU also suggests that whether future inhibitor targeting mutant IDH and blocking the D-2HG production should be used in combination with PCV need to be investigated. In addition to glioma, IDH1 and IDH2 mutations also occur at high frequency in several other types of human malignancies. There is no obvious reason that sensitization to DNA alkylating agents conferred by mutant IDH and D-2-HG is unique to glioma. We have demonstrated in this study that chondrosarcoma cells harboring IDH1 mutation are sensitive to alkylating agent in a manner that is dependent on the mutant IDH1. A number of FDA-approved DNA alkylating agents, such as CCNU and busulfan, have long been used in clinical for cancer treatment. They may merit for further exploration for treatment of other IDH-mutated tumors.
    Experimental Procedures Please refer to Supplemental Experimental Procedures for more detailed information about procedures for protein expression and purification; in vitro ALKBH2 and ALKBH3 activity assay; cell culture, treatment, transfection, viability assay; metabolite extraction and LC-MS/MS analysis of nucleosides.