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Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia
Weiguo Zhang1, Marina Konopleva, Yue-xi Shi
1Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Background:
Internal tandem duplication (ITD) mutations in the juxtamembrane domain-coding sequence of the Fms-like tyrosine kinase 3 (FLT3) gene have been identified in 30% of acute myeloid leukemia (AML) patients and are associated with a poor prognosis. The kinase inhibitor sorafenib induces growth arrest and apoptosis at much lower concentrations in AML cell lines that harbor FLT3-ITD mutations than in AML cell lines with wild-type FLT3.
Methods:
The antileukemic activity of sorafenib was investigated in isogenic murine Ba/F3 AML cell lines that expressed mutant (ITD, D835G, and D835Y) or wild-type human FLT3, in primary human AML cells, and in a mouse leukemia xenograft model. Effects of sorafenib on apoptosis and signaling in AML cell lines were investigated by flow cytometry and immunoblot analysis, respectively, and the in vivo effects were determined by monitoring the survival of leukemia xenograft-bearing mice treated with sorafenib (groups of 15 mice). In a phase 1 clinical trial, 16 patients with refractory or relapsed AML were treated with sorafenib on different dose schedules. We determined their FLT3 mutation status by a polymerase chain reaction assay and analyzed clinical responses by standard criteria. All statistical tests were two-sided.
Results:
Sorafenib was 1000- to 3000-fold more effective in inducing growth arrest and apoptosis in Ba/F3 cells with FLT3-ITD or D835G mutations than in Ba/F3 cells with FLT3-D835Y mutant or wild-type FLT3 and inhibited the phosphorylation of tyrosine residues in ITD mutant but not wild-type FLT3 protein. In a mouse model, sorafenib decreased the leukemia burden and prolonged survival (median survival in the sorafenib-treated group vs the vehicle-treated group = 36.5 vs 16 days, difference = 20.5 days, 95% confidence interval = 20.3 to 21.3 days; P = .0018). Sorafenib reduced the percentage of leukemia blasts in the peripheral blood and the bone marrow of AML patients with FLT3-ITD (median percentages before and after sorafenib: 81% vs 7.5% [P = .016] and 75.5% vs 34% [P = .05], respectively) but not in patients without this mutation.
Conclusion:
Sorafenib may have therapeutic efficacy in AML patients whose cells harbor FLT3-ITD mutations.
Insights
Sorafenib effectively targets acute myeloid leukemia (AML) cells with FLT3-ITD mutations, significantly reducing leukemia burden and improving survival in preclinical models and patients. This kinase inhibitor shows therapeutic promise for AML patients harboring these specific genetic alterations.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Internal tandem duplication (ITD) mutations in FLT3 are common in acute myeloid leukemia (AML) and linked to poor prognosis.
- The kinase inhibitor sorafenib demonstrates differential sensitivity in AML cell lines based on FLT3 mutation status.
Purpose of the Study:
- To investigate the antileukemic activity of sorafenib in AML models with varying FLT3 mutations.
- To evaluate the efficacy of sorafenib in preclinical AML models and a Phase 1 clinical trial.
Main Methods:
- Testing sorafenib in isogenic murine Ba/F3 AML cell lines with wild-type or mutant FLT3 (ITD, D835G, D835Y).
- Assessing sorafenib's effects on apoptosis and signaling via flow cytometry and immunoblotting.
- Evaluating in vivo efficacy in a mouse leukemia xenograft model and a Phase 1 clinical trial in relapsed/refractory AML patients.
Main Results:
- Sorafenib was 1000- to 3000-fold more effective against FLT3-ITD and D835G mutant cells than wild-type or D835Y mutant cells.
- In mice, sorafenib reduced leukemia burden and prolonged survival (median 36.5 vs 16 days).
- In AML patients with FLT3-ITD, sorafenib significantly reduced leukemia blasts in peripheral blood and bone marrow.
Conclusions:
- Sorafenib exhibits significant antileukemic activity in AML models harboring FLT3-ITD mutations.
- Sorafenib demonstrates potential therapeutic efficacy in AML patients with FLT3-ITD mutations.
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