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- Title
Receptor kinase profiles identify a rationale for multitarget kinase inhibition in immature T-ALL.
- Authors
Lhermitte, L; Ben Abdelali, R; Villarèse, P; Bedjaoui, N; Guillemot, V; Trinquand, A; Libura, M; Bedin, A S; Petit, A; Dombret, H; Leverger, G; Ifrah, N; Hermine, O; Macintyre, E; Asnafi, V
- Abstract
Constitutively activated FLT3 signaling is common in acute myeloid leukemia, and is currently under evaluation for targeted therapy, whereas little data is available in T-cell acute lymphoblastic leukemia (T-ALL). We analyzed 357 T-ALL cases for FLT3 mutations and transcript expression. FLT3 mutations (3% overall) and overexpression (FLT3 high expresser (FLT3High)) were restricted to immature/TCRγδ T-ALLs. In vitro FLT3 inhibition induced apoptosis in only 30% of FLT3High T-ALLs and did not correlate with mutational status. In order to investigate the mechanisms of primary resistance to FLT3 inhibition, a broad quantitative screen for receptor kinome transcript deregulation was performed by Taqman Low Density Array. FLT3 deregulation was associated with overexpression of a network of receptor kinases (RKs), potentially responsible for redundancies and sporadic response to specific FLT3 inhibition. In keeping with this resistance to FLT3 inhibition could be reversed by dual inhibition of FLT3 and KIT with a synergistic effect. We conclude that immature T-ALL may benefit from multitargeted RK inhibition and that exploration of the receptor kinome defines a rational strategy for testing multitarget kinase inhibition in malignant diseases.
- Subjects
ACUTE myeloid leukemia treatment; LYMPHOBLASTIC leukemia; KINASE inhibitors; GENETIC mutation; APOPTOSIS; T cells; DRUG receptors
- Publication
Leukemia (08876924), 2013, Vol 27, Issue 2, p305
- ISSN
0887-6924
- Publication type
Article
- DOI
10.1038/leu.2012.177