The effects of lestaurtinib (CEP701) and PKC412 on primary AML blasts: the induction of cytotoxicity varies with dependence on FLT3 signaling in both FLT3-mutated and wild-type cases.
The receptor tyrosine kinase FLT3 is a promising molecular therapeutic target in acute myeloid leukemia (AML). Activating mutations of FLT3 are present in approximately one-third of patients, while many nonmutants show evidence of FLT3 activation, which appears to play a significant role in leukemogenesis. We studied the effects of lestaurtinib (CEP701) and PKC412, 2 small molecule inhibitors of FLT3, on 65 diagnostic AML blast samples. Both agents induced concentration-dependent cytotoxicity in most cases, although responses to PKC412 required higher drug concentrations. Cytotoxic responses were highly heterogeneous and were only weakly associated with FLT3 mutation status and FLT3 expression. Importantly, lestaurtinib induced cytotoxicity in a synergistic fashion with cytarabine, particularly in FLT3 mutant samples. Both lestaurtinib and PKC412 caused inhibition of FLT3 phosphorylation in all samples. Translation of FLT3 inhibition into cytotoxicity was influenced by the degree of residual FLT3 phosphorylation remaining and correlated with deactivation of STAT5 and MAP kinase. FLT3 mutant and wild-type cases both varied considerably in their dependence on FLT3 signaling for survival. These findings support the continued clinical assessment of FLT3 inhibitors in combination with cytotoxic chemotherapy: Entry to future clinical trials should include FLT3 wild-type patients and should remain unrestricted by FLT3 expression level.
Knapper
Steven
S
Department of Haematology, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XW, United Kingdom. knappers@cf.ac.uk
Mills
Kenneth I
KI
Gilkes
Amanda F
AF
Austin
Steve J
SJ
Walsh
Val
V
Burnett
Alan K
AK
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D001752:Blast Crisis / Q000473:pathology; D002227:Carbazoles / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005663:Furans; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000502:physiology
D002227:Carbazoles; D005663:Furans; D007211:Indoles; C119379:lestaurtinib; C497970:FLT3 protein, human; D011505:Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D011493:Protein Kinase C; D019311:Staurosporine; C059539:midostaurin