title: A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response.
abstract: Internal tandem duplication mutations of FLT3 (FLT3/ITD mutations) are common in acute myeloid leukemia (AML) and confer a poor prognosis. This would suggest that FLT3 is an ideal therapeutic target, but FLT3 targeted therapy has produced only modest benefits in clinical trials. Due to technical obstacles, the assessment of target inhibition in patients treated with FLT3 inhibitors has been limited and generally only qualitative. KW-2449 is a novel multitargeted kinase inhibitor that induces cytotoxicity in Molm14 cells (which harbor an FLT3/ITD mutation). The cytotoxic effect occurs primarily at concentrations sufficient to inhibit FLT3 autophosphorylation to less than 20% of its baseline. We report here correlative data from a phase 1 trial of KW-2449, a trial in which typical transient reductions in the peripheral blast counts were observed. Using quantitative measurement of FLT3 inhibition over time in these patients, we confirmed that FLT3 was inhibited, but only transiently to less than 20% of baseline. Our results suggest that the failure to fully inhibit FLT3 in sustained fashion may be an underlying reason for the minimal success of FLT3 inhibitors to date, and stress the importance of confirming in vivo target inhibition when taking a targeted agent into the clinical setting.
authors.affiliation: Department of Oncology, Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Pratz
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Gail J
authors.initials: GJ
authors.lastname: Roboz
authors.forename: Niranjan
authors.initials: N
authors.lastname: Rao
authors.forename: Omotayo
authors.initials: O
authors.lastname: Arowojolu
authors.forename: Adam
authors.initials: A
authors.lastname: Stine
authors.forename: Yukimasa
authors.initials: Y
authors.lastname: Shiotsu
authors.forename: Aiko
authors.initials: A
authors.lastname: Shudo
authors.forename: Shiro
authors.initials: S
authors.lastname: Akinaga
authors.forename: Donald
authors.initials: D
authors.lastname: Small
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.forename: Mark
authors.initials: M
authors.lastname: Levis
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3