Therapy of acute myeloid leukemia: therapeutic targeting of tyrosine kinases

Expert Opin Investig Drugs. 2019 Apr;28(4):337-349. doi: 10.1080/13543784.2019.1584610. Epub 2019 Feb 27.

Abstract

Introduction: Tyrosine kinases (TKs) drive cell survival and proliferation in many normal and malignant cell types. TKs are frequently mutated in acute myeloid leukemia (AML) and hence are increasingly targeted. The management of AML has dramatically improved because of TKI-targeted treatment.

Areas covered: This review provides a biological background for TK inhibitors (TKIs) in AML and reviews their use in the clinic. TK expression and mutation in AML are explored with a focus on TKs associated with specific AML subsets and treatment outcomes. TKIs that specifically target FLT3, c-Kit, and Jak2 are discussed. TKI targeting of specific genes mutated in individual cases and general 'untargeted' use of these agents are highlighted. Lastly, the mechanisms TKI drug resistance in AML are explored

Expert opinion: The use of TKIs in the clinic is improving outcomes for many patients. An improved understanding of tyrosine kinase biology and the expanding use of TKIs are likely to dramatically improve outcomes in the coming decade. TKIs and other targeted agents could gradually supplant the use of cytotoxic chemotherapy for AML.

Keywords: Acute myeloid leukemia; FLT3; targeted therapy; tyrosine kinase.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Humans
  • Janus Kinase 2 / antagonists & inhibitors
  • Janus Kinase 2 / metabolism
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / enzymology
  • Molecular Targeted Therapy
  • Mutation
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-kit / antagonists & inhibitors
  • Proto-Oncogene Proteins c-kit / metabolism
  • fms-Like Tyrosine Kinase 3 / antagonists & inhibitors
  • fms-Like Tyrosine Kinase 3 / metabolism

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • FLT3 protein, human
  • KIT protein, human
  • Proto-Oncogene Proteins c-kit
  • fms-Like Tyrosine Kinase 3
  • JAK2 protein, human
  • Janus Kinase 2