Tuesday 2 September 2008
Definition: Dasatinib is a dual inhibitor of the src and abl tyrosine kinases. It was approved by the Federal Drug Administration for the treatment of imatinib mesylate-resistant chronic myeloid leukemia.
Dasatinib inhibits juxtamembrane domain mutant KIT-D816V autophosphorylation and KIT-dependent activation of down stream signaling important for cell growth and survival of neoplastic cells.
Additionally, dasatinib induces apoptosis in mast cell and leukemia cell lines expressing KIT-D816V.
Dasatinib has in vitro and in vivo efficacy in SM-AML patients with KIT(D816V) mutation. Along with chemotherapy, dasatinib should be considered in these patients particularly if they cannot undergo allogeneic stem cell transplantation for this poor prognostic AML. (18986703)
SRC pathway inhibitors
Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006;354:2531-2541.
Chemotherapy and dasatinib induce long-term hematologic and molecular remission in systemic mastocytosis with acute myeloid leukemia with KIT D816V. Ustun C, Corless CL, Savage N, Fiskus W, Manaloor E, Heinrich MC, Lewis G, Ramalingam P, Kepten I, Jillella A, Bhalla K. Leuk Res. 2009 May;33(5):735-41. PMID: 18986703
Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005;7:129-141.