Strategies targeting FLT3 beyond the kinase inhibitors

Acute myeloid leukemia (AML) is a hematological malignancy characterized by clonal expansion and differentia-tion arrest of the myeloid progenitor cells, which leads to the accumulation of immature cells called blasts in the bone marrow and peripheral blood. Mutations in the receptor tyrosine kinase FLT3 occur in 30% of normal karyo-type patients with AML and are associated with a higher incidence of relapse and worse survival. Targeted thera-pies against FLT3 mutations using small-molecule FLT3 tyrosine kinase inhibitors (TKIs) have long been investigated, with some showing favorable clinical outcomes. However, major setbacks such as limited clinical ef-ficacy and the high risk of acquired resistance remain unresolved. FLT3 signaling, mutations, and FLT3 inhibitors are topics that have been extensively reviewed in recent years. Strategies to target FLT3 beyond the small molecule kinase inhibitors are expanding, nevertheless they are not receiving enough attention. These modalities include antibody-based FLT3 targeted therapies, immune cells mediated targeting strategies, and approaches targeting downstream signaling pathways and FLT3 translation. Here, we review the most recent advances and the chal-lenges associated with the development of therapeutic modalities targeting FLT3 beyond the kinase inhibitors. (c) 2021 Published by Elsevier Inc.

Automated summary

Acute myeloid leukemia is characterized by clonal expansion and differentiation arrest of myeloid progenitor cells, with FLT3 mutations occurring in 30% of AML patients. Targeted therapies against FLT3 mutations using small-molecule inhibitors have shown promising outcomes, but challenges such as acquired resistance persist. Strategies beyond kinase inhibitors, including antibody-based therapies and immune cell mediated targeting, are being explored to address these challenges.