RESUMEN
Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPα-induced fatty acid ß-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBPα methylation, it failed to reverse FAO and OxPHOS. These mitochondrial activities were maintained through the inhibition of Akt and enhanced activation of peroxisome proliferator-activated receptor-γ coactivator-1 PGC1α upon IDH1 mutant inhibitor. Accordingly, OxPHOS inhibitors improved anti-AML efficacy of IDH mutant inhibitors in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors.
Asunto(s)
Resistencia a Antineoplásicos/genética , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide/genética , Mitocondrias/genética , Mutación , Enfermedad Aguda , Aminopiridinas/farmacología , Animales , Línea Celular Tumoral , Doxiciclina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Epigénesis Genética/efectos de los fármacos , Glicina/análogos & derivados , Glicina/farmacología , Células HL-60 , Humanos , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Isocitrato Deshidrogenasa/metabolismo , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/metabolismo , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Oxadiazoles/farmacología , Fosforilación Oxidativa/efectos de los fármacos , Piperidinas/farmacología , Piridinas/farmacología , Triazinas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
There are numerous applications that use the structures of protein-ligand complexes from the PDB, such as 3D pharmacophore identification, virtual screening, and fragment-based drug design. The structures underlying these applications are potentially much more informative if they contain biologically relevant bound ligands, with high similarity to the cognate ligands. We present a study of ligand-enzyme complexes that compares the similarity of bound and cognate ligands, enabling the best matches to be identified. We calculate the molecular similarity scores using a method called PARITY (proportion of atoms residing in identical topology), which can conveniently be combined to give a similarity score for all cognate reactants or products in the reaction. Thus, we generate a rank-ordered list of related PDB structures, according to the biological similarity of the ligands bound in the structures.