FLT3 Inhibitors in Acute Myeloid Leukemia
FLT3 Inhibitors in Acute Myeloid Leukemia
The fms-like tyrosine kinase 3 (FLT3) plays an important role in both normal and malignant hematopoiesis. Activating mutations in the FLT3 receptor can be detected in approximately 30% of acute myeloid leukemias (AMLs) and are associated with a distinctly poor clinical outcome for patients. There are now several classes of FLT3 inhibitors in development with varying degrees of potency and selectivity for the target, including several in late-phase clinical trials in combination with chemotherapy. Major clinical responses in AML patients receiving single-agent FLT3 inhibitors have been rare, although transient peripheral blood blast reduction is common. Given such biological suggestion and preclinical activity, FLT3 inhibitors hold promise in improving the outcome of patients with mutant FLT3 AML. This review summarizes the current attempts to target this molecule, with emphasis on the validity of the target, the results of the clinical trials evaluating the FLT3 inhibitors in AML, the optimal use of these compounds and the mechanisms of resistance.
Receptor tyrosine kinases are transmembrane proteins that generally include an extracellular ligand-binding domain, a membrane-spanning domain and a catalytic cytoplasmic tyrosine kinase domain (TKD). Receptor tyrosine kinases share many important features that are important in understanding their roles in both normal and abnormal cellular function: first, they bind specific ligands that are either proteins or peptides. Second, ligand binding often induces dimerization of the receptor. Third, activation of these receptors requires covalent phosphorylation of the tyrosine residues in the catalytic domain. Fourth, phosphorylation through the addition of a phosphate moiety in the form of GTP in exchange for GDP results in conformational changes crucial for the regulation of the receptor activity. Last, the mitogenic signals transmitted by the activated receptor-associated tyrosine kinases results in the activation of a multitude of downstream cellular pathways, leading to cell growth and proliferation.
The fact that tyrosine kinases are important pathophysiologically and represent viable therapeutic targets was first demonstrated in hematologic malignancies. Starting with the realization that the product of the Philadelphia chromosome t (9;22) results in a constitutively activated tyrosine kinase (BCR/ABL) that defines chronic myeloid leukemia, to the more recent discoveries that the PDGFRα fusion protein plays a key role in hypereosinophilic syndrome and the gain-of-function mutation of Janus kinase 2 is a critical marker in the otherwise phenotypically heterogeneous myeloproliferative disorders, the mutationally activated kinases have been identified as potential contributors to myeloid oncogenesis. Multiple genetic abnormalities are believed to contribute to the pathophysiology of acute myeloid leukemia (AML). In addition to gain-of-function tyrosine kinase mutations, which promote proliferation, other genetic lesions result in blocked differentiation, altered apoptosis or increased survivability in the stem cell compartment. Interestingly, the abnormalities of each functional group appear to be mutually exclusive of other abnormalities in the same group, yet abnormalities in more than one functional category appear necessary for the full transformation to the acute leukemia phenotype.
Leukemias are ideal diseases to test molecularly targeted therapy. The presence of molecularly defined targets is very closely linked with the clinical leukemia phenotypes. Easily accessible tumor cells allow for real-time tumor sampling for pharmacodynamic monitoring of drug activity with minimal patient discomfort or risk. Together, these features provide an outstanding potential for target validation.
Abstract and Introduction
Abstract
The fms-like tyrosine kinase 3 (FLT3) plays an important role in both normal and malignant hematopoiesis. Activating mutations in the FLT3 receptor can be detected in approximately 30% of acute myeloid leukemias (AMLs) and are associated with a distinctly poor clinical outcome for patients. There are now several classes of FLT3 inhibitors in development with varying degrees of potency and selectivity for the target, including several in late-phase clinical trials in combination with chemotherapy. Major clinical responses in AML patients receiving single-agent FLT3 inhibitors have been rare, although transient peripheral blood blast reduction is common. Given such biological suggestion and preclinical activity, FLT3 inhibitors hold promise in improving the outcome of patients with mutant FLT3 AML. This review summarizes the current attempts to target this molecule, with emphasis on the validity of the target, the results of the clinical trials evaluating the FLT3 inhibitors in AML, the optimal use of these compounds and the mechanisms of resistance.
Introduction
Receptor tyrosine kinases are transmembrane proteins that generally include an extracellular ligand-binding domain, a membrane-spanning domain and a catalytic cytoplasmic tyrosine kinase domain (TKD). Receptor tyrosine kinases share many important features that are important in understanding their roles in both normal and abnormal cellular function: first, they bind specific ligands that are either proteins or peptides. Second, ligand binding often induces dimerization of the receptor. Third, activation of these receptors requires covalent phosphorylation of the tyrosine residues in the catalytic domain. Fourth, phosphorylation through the addition of a phosphate moiety in the form of GTP in exchange for GDP results in conformational changes crucial for the regulation of the receptor activity. Last, the mitogenic signals transmitted by the activated receptor-associated tyrosine kinases results in the activation of a multitude of downstream cellular pathways, leading to cell growth and proliferation.
The fact that tyrosine kinases are important pathophysiologically and represent viable therapeutic targets was first demonstrated in hematologic malignancies. Starting with the realization that the product of the Philadelphia chromosome t (9;22) results in a constitutively activated tyrosine kinase (BCR/ABL) that defines chronic myeloid leukemia, to the more recent discoveries that the PDGFRα fusion protein plays a key role in hypereosinophilic syndrome and the gain-of-function mutation of Janus kinase 2 is a critical marker in the otherwise phenotypically heterogeneous myeloproliferative disorders, the mutationally activated kinases have been identified as potential contributors to myeloid oncogenesis. Multiple genetic abnormalities are believed to contribute to the pathophysiology of acute myeloid leukemia (AML). In addition to gain-of-function tyrosine kinase mutations, which promote proliferation, other genetic lesions result in blocked differentiation, altered apoptosis or increased survivability in the stem cell compartment. Interestingly, the abnormalities of each functional group appear to be mutually exclusive of other abnormalities in the same group, yet abnormalities in more than one functional category appear necessary for the full transformation to the acute leukemia phenotype.
Leukemias are ideal diseases to test molecularly targeted therapy. The presence of molecularly defined targets is very closely linked with the clinical leukemia phenotypes. Easily accessible tumor cells allow for real-time tumor sampling for pharmacodynamic monitoring of drug activity with minimal patient discomfort or risk. Together, these features provide an outstanding potential for target validation.
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