Targeting Tyrosine Kinases in Acute Myeloid Leukemia: Why, Who and How?

Pierre-Yves Dumas,Vanessa Desplat,Arnaud Pigneux,Solène Fernandez,Jean-Max Pasquet,Arnaud Villacreces,Noël Milpied,Amélie V. Guitart,Isabelle Vigon

doi:10.3390/ijms20143429

Abstract

Acute myeloid leukemia (AML) is a myeloid malignancy carrying a heterogeneous molecular panel of mutations participating in the blockade of differentiation and the increased proliferation of myeloid hematopoietic stem and progenitor cells. The historical “3 + 7” treatment (cytarabine and daunorubicin) is currently challenged by new therapeutic strategies, including drugs depending on the molecular landscape of AML. This panel of mutations makes it possible to combine some of these new treatments with conventional chemotherapy. For example, the FLT3 receptor is overexpressed or mutated in 80% or 30% of AML, respectively. Such anomalies have led to the development of targeted therapies using tyrosine kinase inhibitors (TKIs). In this review, we document the history of TKI targeting, FLT3 and several other tyrosine kinases involved in dysregulated signaling pathways.

Highlights

Medicine has traveled a long way since the end of the nineteenth century, when blast cells were characterized in the bone marrow of acute myeloid leukemia (AML) patients
FMS-like TK 3 (FLT3) encodes a class III receptor TK (RTK) that is well expressed in hematopoietic stem and progenitor cell (HSPC) and activates the PI3K/AKT and MAPK pathways upon ligand binding
For the last forty years, AML treatment has been limited to intensive chemotherapy with cytarabine and anthracycline

Summary

Introduction

Medicine has traveled a long way since the end of the nineteenth century, when blast cells were characterized in the bone marrow of acute myeloid leukemia (AML) patients. In the last 20 years, the treatment of AML has not kept step with knowledge about the molecular abnormalities leading to leukemogenesis, despite intensive academic and industrial research. While the prognostic classification of AML has improved, therapeutic management is still a matter of debate. Targeted therapies including tyrosine kinase inhibitors (TKIs) are regularly used. Others are still in development to achieve better results in this difficult-to-treat disease

Kinome and Tyrosine Kinase

Tyrosine Kinase in Hematopoietic Tissue

Tyrosine Kinase in Acute Myeloid Leukemia

Tyrosine Kinase Inhibitors

KIT Tyrosine Kinase Inhibitors

TAM Tyrosine Kinase Inhibitors

SYK Tyrosine Kinase Inhibitors

SFK Tyrosine Kinase Inhibitors

TEC Family Tyrosine Kinase Inhibitors

Findings

Concluding Remarks