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  • The unique property of mutant IDH

    2020-07-27

    The unique property of mutant IDH1/2 in producing an oncometabolite that has no known physiological function makes mutant IDH adiponectin receptor 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 cells (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 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.