title: Receptor kinase profiles identify a rationale for multitarget kinase inhibition in immature T-ALL.
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 (FLT3(High))) were restricted to immature/TCRγδ T-ALLs. In vitro FLT3 inhibition induced apoptosis in only 30% of FLT3(High) 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.
authors: Department of Hematology, Hôpital Necker-Enfants-Malades APHP, CNRS UMR 8147, Université Paris-5 Descartes, Paris, France.
authors: L
authors: L
authors: Lhermitte
authors: R
authors: R
authors: Ben Abdelali
authors: P
authors: P
authors: Villarèse
authors: N
authors: N
authors: Bedjaoui
authors: V
authors: V
authors: Guillemot
authors: A
authors: A
authors: Trinquand
authors: M
authors: M
authors: Libura
authors: A S
authors: AS
authors: Bedin
authors: A
authors: A
authors: Petit
authors: H
authors: H
authors: Dombret
authors: G
authors: G
authors: Leverger
authors: N
authors: N
authors: Ifrah
authors: O
authors: O
authors: Hermine
authors: E
authors: E
authors: Macintyre
authors: V
authors: V
authors: Asnafi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects*; D002648:Child; D002675:Child, Preschool; D004273:DNA, Neoplasm / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; D047428:Protein Kinase Inhibitors; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3