FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm beyond inhibitor development

• Published in: Cancer science Vol. 111; no. 2; pp. 312 - 322
• Main Authors: Kiyoi, Hitoshi, Kawashima, Naomi, Ishikawa, Yuichi
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.02.2020; John Wiley and Sons Inc
• Subjects: Acute myeloid leukemia; AKT protein; Apoptosis; Bone marrow; Cell differentiation; Cell growth; Cell proliferation; Cell survival; Chemotherapy; Clinical trials; Clinical Trials as Topic; Clonal deletion; Dimerization; Drug Resistance, Neoplasm; FLT3 gene; fms-Like Tyrosine Kinase 3 - chemistry; fms-Like Tyrosine Kinase 3 - genetics; FMS‐like tyrosine kinase; Gene deletion; Hematopoietic stem cells; Humans; inhibitor; Intracellular signalling; Kinases; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Ligands; MAP kinase; Medical prognosis; Mutants; Mutation; Myeloid leukemia; Phosphorylation; Point Mutation; Protein Domains; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase receptors; resistance; Review; Segmental Duplications, Genomic; Sequence Deletion; Signal Transduction - drug effects; Stat5 protein; Stem cell transplantation; Stem cells; Studies; tyrosine kinase; Japan; FMS-like tyrosine kinase; acute myeloid leukemia; inhibitor; resistance; tyrosine kinase
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.14274

FMS‐like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase that plays an important role in hematopoietic cell survival, proliferation and differentiation. The most clinically important point is that mutation of the FLT3 gene is the most frequent genetic alteration and a poor prognostic factor in acute myeloid leukemia (AML) patients. There are two major types of FLT3 mutations: internal tandem duplication mutations in the juxtamembrane domain (FLT3‐ITD) and point mutations or deletion in the tyrosine kinase domain (FLT3‐TKD). Both mutant FLT3 molecules are activated through ligand‐independent dimerization and trans‐phosphorylation. Mutant FLT3 induces the activation of multiple intracellular signaling pathways, mainly STAT5, MAPK and AKT signals, leading to cell proliferation and anti–apoptosis. Because high‐dose chemotherapy and allogeneic hematopoietic stem cell transplantation cannot sufficiently improve the prognosis, clinical development of FLT3 kinase inhibitors expected. Although several FLT3 inhibitors have been developed, it takes more than 20 years from the first identification of FLT3 mutations until FLT3 inhibitors become clinically available for AML patients with FLT3 mutations. To date, three FLT3 inhibitors have been clinically approved as monotherapy or combination therapy with conventional chemotherapeutic agents in Japan and/or Europe and United states. However, several mechanisms of resistance to FLT3 inhibitors have already become apparent during their clinical trials. The resistance mechanisms are complex and emerging resistant clones are heterogenous. Further basic and clinical studies are required to establish the best therapeutic strategy for AML patients with FLT3 mutations. Several mechanisms of resistance to FLT3 inhibitors have already become apparent during their clinical trials. The resistance mechanisms are complex and emerging resistant clones are heterogenous.