Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms

Nat Commun. 2019 Jan 16;10(1):244. doi: 10.1038/s41467-018-08263-x.

Abstract

FLT3 mutations are prevalent in AML patients and confer poor prognosis. Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tandem duplications and resistance-conferring tyrosine kinase domain mutations. While crenolanib monotherapy has demonstrated clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. Here, to investigate the mechanisms of crenolanib resistance, we perform whole exome sequencing of AML patient samples before and after crenolanib treatment. Unlike other FLT3 inhibitors, crenolanib does not induce FLT3 secondary mutations, and mutations of the FLT3 gatekeeper residue are infrequent. Instead, mutations of NRAS and IDH2 arise, mostly as FLT3-independent subclones, while TET2 and IDH1 predominantly co-occur with FLT3-mutant clones and are enriched in crenolanib poor-responders. The remaining patients exhibit post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restore crenolanib sensitivity.

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Benzimidazoles / pharmacology*
  • Benzimidazoles / therapeutic use
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics*
  • Drug Screening Assays, Antitumor
  • Epigenesis, Genetic / drug effects
  • Female
  • GTP Phosphohydrolases / genetics
  • HEK293 Cells
  • Humans
  • Inhibitory Concentration 50
  • Isocitrate Dehydrogenase / genetics
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Membrane Proteins / genetics
  • Mice
  • Middle Aged
  • Mutation / drug effects
  • Mutation / genetics
  • Piperidines / pharmacology*
  • Piperidines / therapeutic use
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Pyridones / pharmacology
  • Pyridones / therapeutic use
  • Pyrimidinones / pharmacology
  • Pyrimidinones / therapeutic use
  • Tandem Repeat Sequences / genetics
  • Treatment Outcome
  • Whole Exome Sequencing
  • fms-Like Tyrosine Kinase 3 / genetics*

Substances

  • Benzimidazoles
  • Membrane Proteins
  • Piperidines
  • Protein Kinase Inhibitors
  • Pyridones
  • Pyrimidinones
  • trametinib
  • Isocitrate Dehydrogenase
  • isocitrate dehydrogenase 2, human
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • GTP Phosphohydrolases
  • NRAS protein, human
  • crenolanib