FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo.
We examined in vivo FLT3 inhibition in acute myeloid leukemia patients treated with chemotherapy followed by the FLT3 inhibitor lestaurtinib, comparing newly diagnosed acute myeloid leukemia patients with relapsed patients. Because we noted that in vivo FLT3 inhibition by lestaurtinib was less effective in the relapsed patients compared with the newly diagnosed patients, we investigated whether plasma FLT3 ligand (FL) levels could influence the efficacy of FLT3 inhibition in these patients. After intensive chemotherapy, FL levels rose to a mean of 488 pg/mL on day 15 of induction therapy for newly diagnosed patients, whereas they rose to a mean of 1148 pg/mL in the relapsed patients. FL levels rose even higher with successive courses of chemotherapy, to a mean of 3251 pg/mL after the fourth course. In vitro, exogenous FL at concentrations similar to those observed in patients mitigated FLT3 inhibition and cytotoxicity for each of 5 different FLT3 inhibitors (lestaurtinib, midostaurin, sorafenib, KW-2449, and AC220). The dramatic increase in FL level after chemotherapy represents a possible obstacle to inhibiting FLT3 in this clinical setting. These findings could have important implications regarding the design and outcome of trials of FLT3 inhibitors and furthermore suggest a rationale for targeting FL as a therapeutic strategy.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
Takashi
T
Sato
Xiaochuan
X
Yang
Steven
S
Knapper
Paul
P
White
B Douglas
BD
Smith
Steven
S
Galkin
Donald
D
Small
Alan
A
Burnett
Mark
M
Levis
D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000494:pharmacology / Q000627:therapeutic use; D002227:Carbazoles / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D004336:Drug Antagonism; D005663:Furans; D006801:Humans; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008565:Membrane Proteins / Q000097:blood / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D015337:Multicenter Studies as Topic; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D000077157:Sorafenib; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D002227:Carbazoles; D005663:Furans; D007191:Indazoles; C543891:KW 2449; D008565:Membrane Proteins; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C084881:flt3 ligand protein; D009536:Niacinamide; D000077157:Sorafenib; C119379:lestaurtinib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D019311:Staurosporine; C059539:midostaurin
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