Targeting Oncogenic Activity and Signalling of Mutant Receptor Tyrosine Kinase FLT3.

Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase (RTK) that is involved in cell survival, proliferation, and differentiation of haematopoietic progenitors of lymphoid and myeloid lineages. Oncogenic mutations in the FLT3 gene, resulting in constitutively active FLT3 variants, are frequently found in patients with acute myeloid leukaemia (AML). In particular, patients expressing FLT3 ITD (internal tandem duplications of the juxtamembrane domain of FLT3) correlate with poor patient survival. Targeting FLT3-mutated leukaemic stem cells is therefore a key to the efficient treatment of patients with relapsed/refractory AML. The efficacy of approved tyrosine kinase inhibitors is regularly compromised by various resistance pathways or secondary mutations. Based on the current molecular understanding of aberrant signal transduction pathways and cell transformation, novel alternative treatment approaches can be exploited for therapeutic purposes. In particular, new insights into the regulation of the activity of counteracting protein tyrosine phosphatases (PTPs), the aberrant biogenesis and activation of mutant FLT3 proteins, as well as common factors controlling cell transformation are attractive avenues. This review summarises the current knowledge about the regulation of the oncogenic activities of mutant FLT3 proteins and discusses possible options for alternative treatments.