Investigation of the synergistic effect of midostaurin, a tyrosine kinase inhibitor, with anti FLT3 antibodies-based therapies for acute myeloid leukemia

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Saudi Digital Library

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Mutations in the FMS-related tyrosine kinase 3 (FLT3) receptor have been extensively investigated over the past two decades due to their importance as prognostic markers and therapeutic targets in AML. Two main types of recurrent mutations occur in the FLT3 gene: Internal tandem duplication representing the majority of FLT3 mutations (FLT3-ITD about 25% of AML cases), and tyrosine kinase domain mutation (FLT3-TKD, about 10% of AML cases). The FLT3ITD is associated with a high leukemic burden and an unfavorable prognosis. Therefore, in an effort for targeted therapy, anti-FLT3 antibodies and small-molecule FLT3 tyrosine kinase inhibitors were developed and reported promising preclinical and clinical efficacy. However, their efficacy was suboptimal, and these treatments were associated with limited improvement in overall survival. Accumulating evidence suggests that FLT3 inhibitors while downregulating the phosphorylated mutant FLT3 they upregulate the surface expression of FLT3 receptor. This increase in FLT3 expression on the surface may be leveraged to enhance the recognition for antiFLT3 antibody and potentially improve their antileukemia activity. in order to test this approach, we investigated the dual-therapy effect of midostaurin with an in-house manufactured anti-FLT3 single-chain variable fragment (FLT3-scFv) to assess the in vitro ability of binding to FLT3 and reducing the viability of FLT3-ITD cell line (MV4-11). Our findings indicate that the midostaurin treatment increased the expression of FLT3 on the cell surface. In addition, the reduction of cell viability was higher in dual therapy treated cells compared with either treatment alone. These results provide the basis supporting the combination of TKI with FLT3-directed antibody treatment and warrant further preclinical in vivo investigations to validate the in vitro studies.

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