Mechanisms of resistance to FLT3 inhibitors

S. Haihua Chu, Donald Small

Research output: Contribution to journalArticlepeer-review

Abstract

The success of the small molecule tyrosine kinase receptor inhibitor (TKI) imatinib mesylate (Gleevec) in the treatment of chronic myeloid leukemia (CML) constitutes an eminent paradigm shift advocating the rational design of cancer therapeutics specifically targeting the transformation events that drive tumorigenicity. In acute myeloid leukemias (AMLs), the most frequent identified transforming events are activating mutations in the FLT3 receptor tyrosine kinase that constitutively activate survival and proliferation pathways. FLT3 TKIs that are in various phases of clinical trials are showing some initial promise. However, primary and secondary acquired resistance stands to severely compromise long-term and durable efficacy of these inhibitors as a therapeutic strategy. Here, we discuss the mechanisms of resistance to FLT3 inhibitors and possible strategies to overcome resistance through closer examination of the events of leukemogenesis and design of combination therapy.

Original languageEnglish (US)
Pages (from-to)8-16
Number of pages9
JournalDrug Resistance Updates
Volume12
Issue number1-2
DOIs
StatePublished - Feb 2009

Keywords

  • AC220
  • AML
  • CEP701
  • Combination therapy
  • KW-2449
  • Leukemic stem cells
  • MLN518
  • Multitargeted agents
  • NF-κB inhibition
  • PKC412
  • SU-5416
  • SU11248

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Cancer Research
  • Infectious Diseases
  • Pharmacology (medical)

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