Targeting Oncogenic Signaling in Mutant FLT3 Acute Myeloid Leukemia: The Path to Least Resistance

Abstract

The identification of recurrent driver mutations in genes encoding tyrosine kinases has resulted in the development of molecularly-targeted treatment strategies designed to improve outcomes for patients diagnosed with acute myeloid leukemia (AML). The receptor tyrosine kinase FLT3 is the most commonly mutated gene in AML, with internal tandem duplications within the juxtamembrane domain (FLT3-ITD) or missense mutations in the tyrosine kinase domain (FLT3-TKD) present in 30–35% of AML patients at diagnosis. An established driver mutation and marker of poor prognosis, the FLT3 tyrosine kinase has emerged as an attractive therapeutic target, and thus, encouraged the development of FLT3 tyrosine kinase inhibitors (TKIs). However, the therapeutic benefit of FLT3 inhibition, particularly as a monotherapy, frequently results in the development of treatment resistance and disease relapse. Commonly, FLT3 inhibitor resistance occurs by the emergence of secondary lesions in the FLT3 gene, particularly in the second tyrosine kinase domain (TKD) at residue Asp835 (D835) to form a ‘dual mutation’ (ITD-D835). Individual FLT3-ITD and FLT3-TKD mutations influence independent signaling cascades; however, little is known about which divergent signaling pathways are controlled by each of the FLT3 specific mutations, particularly in the context of patients harboring dual ITD-D835 mutations. This review provides a comprehensive analysis of the known discrete and cooperative signaling pathways deregulated by each of the FLT3 specific mutations, as well as the therapeutic approaches that hold the most promise of more durable and personalized therapeutic approaches to improve treatments of FLT3 mutant AML.

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

“…In turn, LSCs give rise to a large population of immature leukemic blasts characterized by multiple epigenetic and genetic alterations [84][85][86]. These changes lead to aberrant activation of several signaling pathways that contribute to AML pathogenesis and progression [87][88][89][90]. In general, alterations in genes encoding epigenetic regulators are usually acquired earlier and are detectable in the founding pre-leukemic clone [84,85].…”

Mutation profiling of anaplastic ependymoma grade III by Ion Proton next generation DNA sequencing

“…This variant is not reported in the COSMIC database or dbSNP also. The most common form of FLT3 mutation is in the internal tandem duplication (ITD) region of the juxta-membrane domain (AA 572-609), which occurs in 15-35% of patients with AML (Staudt et al, 2018). The presence of either a FLT3 ITD or TKD mutation may be associated with a response to the tyrosine kinase inhibitor, Midostaurin (Stone et al, 2017).…”

Signal Transduction in Diffuse Intrinsic Pontine Glioma

“…However, as is seen in more frequently studied cancers, individual driver mutations, and those either induced or selected for by therapeutic interventions like in acute myeloid leukemia, drive the activity of divergent signaling pathways that are impossible to predict using genomic approaches (reviewed in ref. []).…”