Gain-of-function mutations of isocitrate dehydrogenase 1 ( IDH1 ) lead to oncometabolite ( R )-2-hydroxyglutarate production, contributing to the tumorigenesis of multiple human cancers. While fatty acid biosynthesis is critical for IDH1 -mutant tumor growth, the underlying mechanisms remain unclear. Here, leveraging chemical probes and chemoproteomic profiling, we identified that oncogenic IDH1-R132H is uniquely autopalmitoylated at C269, which is not observed in wild-type IDH1. This modification responds to fatty acids and regulates R132H enzymatic activity by enhancing substrate and cofactor binding, as well as dimerization. Loss of C269 palmitoylation reverses IDH1-R132H-induced metabolic reprogramming and hypermethylation phenotypes and impairs cell transformation. Interestingly, C269 autopalmitoylation occurs within a hydrophobic pocket, targeted by a clinical IDH1 -mutant inhibitor (LY3410738). Our study reveals that autopalmitoylation, conferred by the IDH1 R132H mutation, links fatty acid metabolism to the regulation of IDH1 mutant activity and represents a druggable vulnerability in IDH1 -mutant cancers.
Hu et al. (Tue,) studied this question.