In vitro and in vivo study of ABT-869 in treatment acute myeloid leukemia (AML) alone or in combination with chemotherapy or HDAC inhibitors: insight into molecular mechanism and biologic characterization

Abstract

Internal tandem duplications (ITDs) of fms-like tyrosine kinase 3 (FLT3) receptor play an important role in the pathogenesis of AML and represent an attractive therapeutic target. We first demonstrate ABT-869, a multi-targeted receptor tyrosine kinase inhibitor (TKI) as a potent FLT3 inhibitor. ABT-869 demonstrates significant sequence dependent synergism with cytarabine and doxorubicin. Low density array (LDA) analysis revealed the synergistic interaction involved in down-regulation of cell cycle and MAPK pathway genes. ABT-869 also reduced the FLT3 wide type leukemia burden and prolonged survival. Next we discovered that enhanced activation of STAT pathways and overexpression of survivin are the main mechanism of resistance to ABT-869, suggesting potential targets for reducing resistance developed in patients receiving FLT3 inhibitors.We demonstrated that combining ABT-869 with SAHA leaded to synergistic killing of AML cells with FLT3 mutations. Our results suggest such combination therapies may significantly improve the therapeutic efficacy of FLT3 inhibitors in clinic.