Predicting Response To Idh1/Idh2 Inhibitors Beyond Idh Mutations Using A Computational Model And Its Validation: A Beat Aml Project Study

Background: Isocitrate dehydrogenase (IDH) is an essential enzyme in the TCA cycle. Recurrent mutations in IDH1 or IDH2 are prevalent in several cancers, including glioma and acute myeloid leukemia (AML). IDH mutations reduce cellular levels of α-ketoglutarate (α-KG), resulting in accumulation of 2-hydroxyglutarate (2-HG), an α-KG antagonist. This leads to the inhibition of both α-KG-dependent histone lysine demethylases and the TET family of DNA hydroxylases. Even though current IDH inhibitors have high specificity towards the IDH1 and IDH2 mutant forms, the overall clinical response rate to these drugs remains ~19%, suggesting the presence of IDH mutations alone does not reflect positive clinical outcome. However, defining biomarkers and developing methods to predict response to IDH inhibitors will expedite the drug development process and provide patient selection criteria for future clinical trials.