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Receptor kinase profiles identify a rationale for multitarget kinase inhibition in immature T-ALL

L Lhermitte1, R Ben Abdelali, P Villarèse

  • 1Department of Hematology, Hôpital Necker-Enfants-Malades APHP, CNRS UMR 8147, Université Paris-5 Descartes, Paris, France.

Leukemia
|July 4, 2012
PubMed

Insights

Constitutively activated FLT3 signaling, common in acute myeloid leukemia, is less understood in T-cell acute lymphoblastic leukemia (T-ALL). FLT3 inhibition showed limited efficacy in T-ALL, suggesting multitargeted receptor kinase inhibition as a promising strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Hematology

Background:

  • Constitutively activated FLT3 signaling is a hallmark of acute myeloid leukemia, with targeted therapies under investigation.
  • Limited data exists on FLT3's role and therapeutic targeting in T-cell acute lymphoblastic leukemia (T-ALL).

Purpose of the Study:

  • To investigate FLT3 mutations, expression, and the efficacy of FLT3 inhibition in T-ALL.
  • To explore mechanisms of primary resistance to FLT3 inhibition and identify alternative therapeutic strategies.

Main Methods:

  • Analysis of FLT3 mutations and transcript expression in 357 T-ALL cases.
  • In vitro FLT3 inhibition assays and quantitative screening of receptor kinome deregulation using Taqman Low Density Array.

Main Results:

  • FLT3 mutations and overexpression were found in immature/TCRγδ T-ALL subtypes.
  • FLT3 inhibition induced apoptosis in only 30% of FLT3(High) T-ALLs, with resistance linked to receptor kinase network deregulation.
  • Dual inhibition of FLT3 and KIT synergistically reversed resistance.

Conclusions:

  • Immature T-ALL may benefit from multitargeted receptor kinase inhibition.
  • Exploration of the receptor kinome is crucial for developing rational multitarget kinase inhibition strategies in T-ALL and other malignancies.

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