Format

Send to

Choose Destination
See comment in PubMed Commons below
Curr Opin Hematol. 2005 Jan;12(1):7-13.

Therapeutic intervention in leukemias that express the activated fms-like tyrosine kinase 3 (FLT3): opportunities and challenges.

Author information

  • 1Division of Hematology/Oncology, Mount Sinai School of Medicine, New York, New York 10029, USA.

Abstract

PURPOSE OF REVIEW:

The fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase is now recognized to be a critical mediator in the pathogenesis of myeloid and some lymphoid leukemias. This article reviews recent efforts to disrupt FLT3 signaling in acute myelogenous leukemia and to identify potential therapeutic challenges posed by the acquisition of resistance mutations in these malignancies.

RECENT FINDINGS:

Several broad classes of FLT3 protein tyrosine kinase inhibitors are undergoing evaluation in clinical trials. Although the agents are well tolerated by patients, clinical responses in relapsed or refractory acute myelogenous leukemia (AML) are limited and transient. Nevertheless, these agents may hold promise when combined with traditional chemotherapy. Use of tyrosine kinase inhibitors for AML therapy is hindered by the acquisition of mutations in the kinase catalytic domain, and in the case of BCR-ABL, these mutations confer resistance to imatinib. In anticipation of this problem, FLT3 mutations that might confer resistance to kinase inhibitors in the clinical setting have already been identified in the laboratory. Strategies to overcome such resistance are currently under development. New efforts focus on blocking the binding of FLT3 ligand to its receptor as a means of inhibiting autocrine stimulation in leukemogenesis.

SUMMARY:

FLT3 is widely expressed in AML and some cases of acute lymphocytic leukemia. Activating mutations in FLT3 confer a poor risk in patients with AML. The development of FLT3 small molecule kinase inhibitors follows from research efforts to understand signal transduction and profiles of gene expression in leukemia pathogenesis. Thus, FLT3 is a promising target for therapeutic intervention. Research priorities will include (1) identification of other groups of patients likely to benefit from FLT3 inhibition, (2) the optimal use of FLT3 inhibitors in combination with other agents, and (3) development of molecules that overcome resistance to FLT3 inhibitors that arise as a result of further acquired mutations in the receptor.

PMID:
15604885
[PubMed - indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Lippincott Williams & Wilkins
    Loading ...
    Support Center