Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations

Nature. 2018 Jul;559(7712):125-129. doi: 10.1038/s41586-018-0251-7. Epub 2018 Jun 27.

Abstract

Somatic mutations in the isocitrate dehydrogenase 2 gene (IDH2) contribute to the pathogenesis of acute myeloid leukaemia (AML) through the production of the oncometabolite 2-hydroxyglutarate (2HG)1-8. Enasidenib (AG-221) is an allosteric inhibitor that binds to the IDH2 dimer interface and blocks the production of 2HG by IDH2 mutants9,10. In a phase I/II clinical trial, enasidenib inhibited the production of 2HG and induced clinical responses in relapsed or refractory IDH2-mutant AML11. Here we describe two patients with IDH2-mutant AML who had a clinical response to enasidenib followed by clinical resistance, disease progression, and a recurrent increase in circulating levels of 2HG. We show that therapeutic resistance is associated with the emergence of second-site IDH2 mutations in trans, such that the resistance mutations occurred in the IDH2 allele without the neomorphic R140Q mutation. The in trans mutations occurred at glutamine 316 (Q316E) and isoleucine 319 (I319M), which are at the interface where enasidenib binds to the IDH2 dimer. The expression of either of these mutant disease alleles alone did not induce the production of 2HG; however, the expression of the Q316E or I319M mutation together with the R140Q mutation in trans allowed 2HG production that was resistant to inhibition by enasidenib. Biochemical studies predicted that resistance to allosteric IDH inhibitors could also occur via IDH dimer-interface mutations in cis, which was confirmed in a patient with acquired resistance to the IDH1 inhibitor ivosidenib (AG-120). Our observations uncover a mechanism of acquired resistance to a targeted therapy and underscore the importance of 2HG production in the pathogenesis of IDH-mutant malignancies.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Allosteric Site / drug effects
  • Allosteric Site / genetics
  • Aminopyridines / chemistry
  • Aminopyridines / pharmacology*
  • Aminopyridines / therapeutic use
  • Animals
  • Clinical Trials, Phase I as Topic
  • Clinical Trials, Phase II as Topic
  • Disease Progression
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Glutamine / genetics
  • Glutarates / blood
  • Glutarates / metabolism
  • HEK293 Cells
  • Humans
  • Isocitrate Dehydrogenase / antagonists & inhibitors*
  • Isocitrate Dehydrogenase / genetics*
  • Isoleucine / genetics
  • Leukemia, Myeloid, Acute / blood
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Mutant Proteins / antagonists & inhibitors
  • Mutant Proteins / genetics*
  • Mutation*
  • Protein Multimerization / genetics*
  • Triazines / chemistry
  • Triazines / pharmacology*
  • Triazines / therapeutic use

Substances

  • Aminopyridines
  • Enzyme Inhibitors
  • Glutarates
  • Mutant Proteins
  • Triazines
  • Isoleucine
  • Glutamine
  • alpha-hydroxyglutarate
  • enasidenib
  • IDH2, human
  • Isocitrate Dehydrogenase