Understanding and imaging PHGDH-driven intrinsic resistance to mutant IDH inhibition in gliomas

Abstract

Mutations in isocitrate dehydrogenase (IDHm) define a distinct molecular class of gliomas. IDHm converts -ketoglutarate (-KG) to the oncometabolite D-2-hydroxyglutarate (D-2HG), which drives tumorigenesis. The IDHm inhibitor vorasidenib suppresses D-2HG production and extends progression-free survival in some, but not all, IDHm glioma patients. Here, using clinically relevant patient-derived IDHm models and patient tissue, we show that phosphoglycerate dehydrogenase (PHGDH) drives intrinsic resistance to vorasidenib by promiscuously converting -KG to D-2HG and maintaining D-2HG concentration despite IDHm inhibition. Silencing PHGDH sensitizes resistant models to vorasidenib, while conversely, overexpressing PHGDH induces vorasidenib resistance in sensitive models. Importantly, deuterium metabolic imaging of D-2HG production from diethyl-[3,3-2H]--ketoglutarate provides an early readout of response and resistance to vorasidenib that is not available by anatomical imaging in vivo. Collectively, we have identified PHGDH-driven D-2HG production as an intrinsic mechanism of resistance to vorasidenib and diethyl-[3,3-2H]-ketoglutarate as a non-invasive tracer for interrogating intrinsic resistance in IDHm gliomas. STATEMENT OF SIGNIFICANCEVorasidenib, which suppresses D-2HG production, is the first precision therapy to be approved for IDHm glioma patients. We show that PHGDH-driven restoration of D-2HG production mediates intrinsic resistance to vorasidenib in IDHm gliomas. Importantly, deuterium metabolic imaging of D-2HG production from diethyl-[3,3-2H]--ketoglutarate enables non-invasive assessment of resistance in IDHm gliomas.