Submitted July 13, 2007
Accepted August 20, 2007
Uniform sensitivity of FLT3 activation loop mutants to the tyrosine kinase inhibitor midostaurin
Elly V. Barry*, Jennifer J. Clark, Jan Cools, Johannes Roesel, and D. Gary Gilliland
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
Children's Hospital Boston, Harvard Medical School, Boston, MA, United States
Department of Molecular and Developmental Genetics, VIB, K. U. Leuven, Leuven, Belgium
Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland
Brigham and Women's Hospital, and the Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, United States
* Corresponding author; email: elly_barry{at}dfci.harvard.edu.
Small molecule inhibitors that target FLT3 activating mutations have potential in the treatment of leukemias. However, certain mutations simultaneously activate the tyrosine kinase, and confer resistance to small molecule inhibitors. We therefore tested the sensitivity of eight FLT3 activation loop mutants to midostaurin. Each mutant conferred IL-3 factor-independent proliferation to Ba/F3 cells, and each resulted in the constitutive activation of FLT3 and its targets, STAT5 and ERK. For each mutant tested, midostaurin inhibited cell growth, and phosphorylation of FLT3, STAT5 and ERK. In contrast, midostaruin did not inhibit Ba/F3 cells stably transduced with FLT3-ITD containing a G697R mutation that confers resistance to midostaurin, demonstrating that midostaurin inhibition of FLT3 activation loop mutants was not due to off-target effects. We conclude that midostaurin is a potent inhibitor of a spectrum of FLT3 activation loop mutations, and that AML patients with such mutations are potential candidates for clinical trials involving midostaurin.
