Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases

Pharmacol Ther. 2018 Nov;191:123-134. doi: 10.1016/j.pharmthera.2018.06.016. Epub 2018 Jun 30.


Mutations within the activation loop of members of the class III receptor tyrosine kinase (RTK) subfamily, which includes KIT, PDGFRA, and FLT3, have been observed in multiple human tumor types. These mutations confer constitutive activation as well as resistance to the type II tyrosine kinase inhibitors (TKI) that are currently clinically available, such as imatinib and sunitinib. It is now understood that activation loop mutations in class III RTKs shift the activation state equilibrium away from inactive states, to which type II TKIs bind, to the active state by destabilizing the inactive conformation. Recently, type I TKIs, which can bind to active kinase conformations, have been developed with specificity for class III RTK members. Some type I TKIs, such as crenolanib and avapritinib (BLU-285), have entered clinical studies for patients with activation loop mutations in KIT, PDGFRA, or FLT3. Preliminary results suggest that these type I TKIs show activity in these patient populations that previously lacked effective treatments. This article reviews the inactive and active structures of KIT, PDGFRA, and FLT3, how the mutations seen in human cancers affect kinase structure, and the clinical implications of these mutations in terms of type I vs. type II TKI binding.

Keywords: Activation loop mutation; KIT; Kinase inhibitor; Kinase inhibitor resistance; PDGFRA; Type I kinase inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Benzimidazoles / pharmacology
  • Drug Development / methods
  • Humans
  • Mutation
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / genetics
  • Piperidines / pharmacology
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-kit / genetics
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • fms-Like Tyrosine Kinase 3 / genetics


  • Antineoplastic Agents
  • Benzimidazoles
  • Piperidines
  • Protein Kinase Inhibitors
  • FLT3 protein, human
  • KIT protein, human
  • Proto-Oncogene Proteins c-kit
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Platelet-Derived Growth Factor alpha
  • fms-Like Tyrosine Kinase 3
  • crenolanib