Mechanisms of Resistance to FLT3 Inhibitors and the Role of the Bone Marrow Microenvironment

Hematol Oncol Clin North Am. 2017 Aug;31(4):681-692. doi: 10.1016/j.hoc.2017.04.005. Epub 2017 May 18.

Abstract

The presence of FLT3 mutations in acute myeloid leukemia (AML) carries a particularly poor prognosis, making the development of FLT3 inhibitors an imperative goal. The last decade has seen an abundance of clinical trials using these drugs alone or in combination with chemotherapy. This culminated with the recent approval by the US Food and Drug Administration of Midostaurin for the treatment of FLT3-mutated AML. Initial success has been followed by the emergence of clinical resistance. Although novel FLT3 inhibitors are being developed, studies into mechanisms of resistance raise hope of new strategies to prevent emergence of resistance and eliminate minimal residual disease.

Keywords: AML; FLT3 inhibitors; FLT3-ITD; Stem cell niche.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Bone Marrow / metabolism*
  • Bone Marrow / pathology*
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cellular Microenvironment / drug effects*
  • Drug Resistance, Neoplasm* / genetics
  • Gene Duplication
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Mutation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Signal Transduction / drug effects
  • Tandem Repeat Sequences
  • fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
  • fms-Like Tyrosine Kinase 3 / genetics
  • fms-Like Tyrosine Kinase 3 / metabolism

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • fms-Like Tyrosine Kinase 3