Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain

Florian Heidel, Fian K. Solem, Frank Breitenbuecher, Daniel B. Lipka, Stefan Kasper, M. H. Thiede, Christian Brandts, Hubert Serve, Johannes Roesel, Francis Giles, Eric Feldman, Gerhard Ehninger, Gary J. Schiller, Stephen Nimer, Richard M. Stone, Yanfeng Wang, Thomas Kindler, Pamela S. Cohen, Christoph Huber, Thomas Fischer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

192 Scopus citations

Abstract

Activating mutations in the FLT3 tyrosine kinase (TK) occur in approximately 35% of patients with acute myeloid leukemia (AML). Therefore, targeting mutated FLT3 is an attractive therapeutic strategy, and early clinical trials testing FLT3 TK inhibitors (TKI) showed measurable clinical responses. Most of these responses were transient; however, in a subset of patients blast recurrence was preceded by an interval of prolonged remission. The etiology of clinical resistance to FLT3-TKI in AML is unclear but is of major significance for the development of future therapeutic strategies. We searched for mechanisms of resistance in 6 patients with AML who had relapses upon PKC412 treatment. In an index AML patient, an algorithm of analyses was applied using clinical material. In vivo and in vitro investigation of primary blasts at relapse revealed persistent TK phosphorylation of FLT3 despite sufficient PKC412 serum levels. Through additional molecular analyses, we identified a single amino acid substitution at position 676 (N676K) within the FLT3 kinase domain as the sole cause of resistance to PKC412 in this patient. Reconstitution experiments expressing the N676K mutant in 32D cells demonstrated that FLT3-ITD-N676K was sufficient to confer an intermediate level of resistance to PKC412 in vitro. These studies point out that a genetically complex malignancy such as AML may retain dependence on a single oncogenic signal.

Original languageEnglish (US)
Pages (from-to)293-300
Number of pages8
JournalBlood
Volume107
Issue number1
DOIs
StatePublished - Jan 1 2006

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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