Altered Signal Transduction In Isocitrate Dehydrogenase (Idh) Mutated Glioblastomas And Implication On Precision Medicine

Glioblastoma (GBM) is the most common form of primary brain cancer and remains one of the most devastating of human diseases. One recurrent physiologic states in glioblastoma is defined by mutation of the Isocitrate Dehydrogenase (IDH) genes. IDH genes encode enzymes that catalyze oxidative decarboxylation of isocitrate. Nearly all IDH mutations in GBM involve substitution of arginine 132 of IDH1 with histidine (IDH1-R132H). The mutant protein loses the capacity to carry out its innate function and instead produces 2-hydroxyglutarate (2HG). The aberrant production of 2HG, in turn, alters the epigenetic landscape in these GBM cells. While it is clear that IDH1 mutated GBMs harbor a distinct cell state, the signaling cascades contributing to this biology remain poorly understood. Using published mRNA signatures associated with EGFR activation, we demonstrate that IDH mutated GBMs harbored decreased EGFR signaling using four different GBM cohorts, including the Chinese Glioma Genome Atlas(CGGA; n = 155), the REMBRANDT dataset (n = 288), The Cancer Genome Atlas (TCGA; n = 406), and the UCSD cohort (n = 25). Further analysis revealed that IDH mutated clinical specimens and cell lines harbored lowered mRNA levels for EGFR and H-Ras. These suppressions were associated with increased deposition of the repressive histone markers, H3K9me3 and H3K27me3, in the EGFR and H-Ras promoter regions. Finally, the exogenous expression of IDH1-R132H conferred resistance to the EGFR inhibitor, Gefitinib, suggesting IDH1 mutation as a predictive biomarker for EGFR inhibitor response in GBM patients. We further analyzed mRNA signatures associated with p53 activation and DNA damage accumulation in IDH mutated GBMs. We found that that IDH mutated specimens exhibited lowered level of signatures associated with p53 activation, suggesting decreased DNA damage accumulation. We subsequently determined whether this state of lowered DNA damage accumulation is associated with altered sensitivity to DNA damaging agents. Exogenous expression of IDH1-R132H in multiple glioblastoma and glial lines conferred increased resistance to temozolomide (TMZ). This resistance is associated with decreased accumulation of γ-H2AX. Consistently, we found that in a prospective glioblastoma registry of 274 GBM patients, IDH mutation is associated with poor response to TMZ (p In contrast to EGFR and p53 signaling, where IDH mutation is associated with pathway suppression, we found an association between elevated MYC expression and IDH mutation in both clinical specimens and cell-line models. Moreover, exogenous IDH1-R132H expression is associated with increased sensitivity to agents that suppress MYC expression, including LSD1 inhibitors. These results suggest potential therapeutic opportunities to target IDH mutated GBMs through epigenetic modulation of MYC expression. Citation Format: Jie Li, Zachary J. Taich, Johnny Akers, Scott Vandenberg, Clark C. Chen. Altered signal transduction in Isocitrate Dehydrogenase (IDH) mutated glioblastomas and implication on precision medicine. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4459.