Membrane Tyrosine Kinase Receptors are an Important Target for the Therapy of Acute Myeloid Leukemia

Ugo      Testa

Abstract

KIT and FLT3 are class III trans membrane tyrosine kinases playing key roles in the control of hematopoietic stem cell survival and proliferation. KIT is mutated in about 2.5-3% of acute myeloid leukemia (AML) patients mainly by point mutations occurring at the level of tyrosine kinase domains. FLT3 is mutated in about 30% of AML patients, either by internal tandem duplication of the juxtamembrane domain or by point mutations occurring at the level of tyrosine kinase domains. All these types of mutations lead to the constitutive activation of KIT and FLT3 receptors, respectively. The occurrence of FLT3/ITD mutation is associated with a poor prognosis. These observations have represented the basis for the development of a relatively large number of Tyrosine Kinase Inhibitors (TKI) with activity against KIT and FLT3. The majority of these inhibitors are still in the preclinical phase of study, while few of them have been tested in phase I/II clinical studies. Although these inhibitors when used as single agents have lead to a significant reduction of the number of leukemic blasts, they have produced only transient and limited clinical responses. This efficacy may be related to the occurrence of resistance and to the complexity of the genetic abnormalities occurring in AMLs. The efficacy of FLT3 TKIs in combination with standard anti-leukemic chemotherapeutics has been evaluated in preclinical models and several combination clinical trials are ongoing and have been planned. It is expected that these trials could determine an improvement in the negative prognosis of AML patients with FLT3/ITD mutations. Finally, the combination of FLT3 TKIs with other molecularly targeted agents inhibiting other pathways activated in leukemic cells would determine a major progress in leukemia therapy.

Keywords: Tyrosine Kinases catalytic domain, Homeobox gene, c-Kit, KIT signaling, juxtamembrane domain, FMS-LIKE TYROSINE KINASE

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