Computer simulations of the signalling network in FLT3 +-acute myeloid leukaemia - indications for an optimal dosage of inhibitors against FLT3 and CDK6

BMC Bioinformatics. 2018 Apr 24;19(1):155. doi: 10.1186/s12859-018-2145-y.

Abstract

Background: Mutations in the FMS-like tyrosine kinase 3 (FLT3) are associated with uncontrolled cellular functions that contribute to the development of acute myeloid leukaemia (AML). We performed computer simulations of the FLT3-dependent signalling network in order to study the pathways that are involved in AML development and resistance to targeted therapies.

Results: Analysis of the simulations revealed the presence of alternative pathways through phosphoinositide 3 kinase (PI3K) and SH2-containing sequence proteins (SHC), that could overcome inhibition of FLT3. Inhibition of cyclin dependent kinase 6 (CDK6), a related molecular target, was also tested in the simulation but was not found to yield sufficient benefits alone.

Conclusions: The PI3K pathway provided a basis for resistance to treatments. Alternative signalling pathways could not, however, restore cancer growth signals (proliferation and loss of apoptosis) to the same levels as prior to treatment, which may explain why FLT3 resistance mutations are the most common resistance mechanism. Finally, sensitivity analysis suggested the existence of optimal doses of FLT3 and CDK6 inhibitors in terms of efficacy and toxicity.

Keywords: Acute myeloid leukaemia; Combination therapy; Drug resistance; Knowledge-based analysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Cell Proliferation / drug effects
  • Computer Simulation*
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 6 / genetics
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology*
  • Mutation
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / standards*
  • Signal Transduction / drug effects
  • fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
  • fms-Like Tyrosine Kinase 3 / genetics

Substances

  • Protein Kinase Inhibitors
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 6