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(A) Structure and activation of FLT3 receptor. FLT3 molecule is a tyrosine kinase receptor composed of an extracellular domain (ECD) that comprises 5 immunoglobuline-like repeats, a short transmembrane domain (TMD) and an intracellular domain (ICD) that includes a juxtramembrane (JM) domain followed by two tyrosine kinase (TK) domains (TK1 and TK2). Binding of the FLT3 ligand (FL) to ECD leads to formation of a ternary complex between FL and two receptor subunits with consequent conformational changes and trans-phosphorylation of TK and JM domains. The activated receptor exerts a tyrosine kinase activity against a series of adaptor and effector molecules leading to activation of Ras/Raf/MAPK (RAS) PI3K/Akt (PI3K) and Jak/STAT5 (STAT5) pathways promoting leukemic cell proliferation and survival and suppressing differentiation. Both FLT3-ITD and FLT3-TKD mutations lead to ligandindependent activation of FLT3 signaling; (B) types of FLT3 inhibitors. Type I FLT3 inhibitors interact with the ATP-binding site of the intracellular TK domain (TKD) when the receptor is in active conformation, whereas Type II inhibitors bind to the inactive form of the receptor, thus preventing its activation. Type I inhibitors inhibit FLT3 signaling in AML cells harboring ITD or TKD mutations, whereas Type II inhibitors are active against AML with ITD but not TKD mutations; (C) mechanisms of primary resistance to FLT3 inhibitors: Increased proliferation and survival and decreased differentiation of AML cells may be sustained through (I) Cytochrome P450 3A4- mediated degradation of FLT3-inhibitors by hepatocytes (liver symbol) and BM stromal cells (BMSC); (II) Restoration of FL/FLT3 signaling through compensatory overexpression of wild-type (WT) FLT3 receptor and FL; (III) Activation of common FLT3 and fibroblast growth factor receptor type 1 (FGFR1) downstream target pathways through the increased fibroblast growth factor 2 (FGF2)/FGFR1 signaling; (D) mechanisms of secondary resistance to FLT3 inhibitors: (I) Secondary resistance of FLT3 receptor to pharmacological inhibition may be conferred through newly acquired activating mutations of FLT3 TKD (red asterisk), and upregulation of pro-survival mechanisms through acquired activating mutations in RAS/MAPK pathway genes (II) and epigenetic modifiers like DNMT3A, TET2, IDH2 or transcriptional regulators like WT1 and TP53 (III). Green and red rectangles correspond to activated and inactivated FLT3 downstream signaling pathways, respectively. Yellow “P” circles indicate phosphorylated receptor domains. Green and red arrows indicate positive and negative regulation, respectively
Source publication
FMS-related tyrosine kinase 3 (FLT3) mutations, present in about 25%-30% of acute myeloid leukemia (AML) patients, constitute one of the most frequently detected mutations in these patients. The binding of FLT3L to FLT3 activates the phosphatidylinositol 3-kinase (PI3K) and RAS pathways, producing increased cell proliferation and the inhibition of...
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Citations
... In AML, RAS mutational status plays a pivotal role in the response to FLT3 inhibitors. For instance, RAS/MAPK pathway mutations emerge in approximately one third of AML patients experiencing disease progression on gilteritinib therapy [75]. A parallel study on crenolanib therapy in relapsed/refractory FLT3-mutated AML also identified epigenetic and genetic alterations, including NRAS mutations, associated with resistance. ...
NRAS and KRAS activating point mutations are present in 10–30% of myeloid malignancies and are often associated with a proliferative phenotype. RAS mutations harbor allele-specific structural and biochemical properties depending on the hotspot mutation, contributing to variable biological consequences. Given their subclonal nature in most myeloid malignancies, their clonal architecture, and patterns of cooperativity with other driver genetic alterations may potentially have a direct, causal influence on the prognosis and treatment of myeloid malignancies. RAS mutations overall tend to be associated with poor clinical outcome in both chronic and acute myeloid malignancies. Several recent prognostic scoring systems have incorporated RAS mutational status. While RAS mutations do not always act as independent prognostic factors, they significantly influence disease progression and survival. However, their clinical significance depends on the type of mutation, disease context, and treatment administered. Recent evidence also indicates that RAS mutations drive resistance to targeted therapies, particularly FLT3, IDH1/2, or JAK2 inhibitors, as well as the venetoclax-azacitidine combination. The investigation of novel therapeutic strategies and combinations that target multiple axes within the RAS pathway, encompassing both upstream and downstream components, is an active field of research. The success of direct RAS inhibitors in patients with solid tumors has brought renewed optimism that this progress will be translated to patients with hematologic malignancies. In this review, we highlight key insights on RAS mutations across myeloid malignancies from the past decade, including their prevalence and distribution, cooperative genetic events, clonal architecture and dynamics, prognostic implications, and therapeutic targeting.
... Among the first-generation and type 1 FLT3 inhibitors, distinguished ones include midostaurin and lestaurtinib, and first-generation type 2 includes sorafenib and tandutinib. Second-generation type 1 inhibitors include gilteritinib and crenolanib, and secondgeneration type 2 include quizartinib [45,49,61]. ...
... Regarding FLT3i classification, sorafenib belongs to 1st generation type 2 FLT3i, which means it is only active against FLT3-ITD AML. Currently, sorafenib is approved for hepatocellular carcinoma and renal cell carcinoma therapy; however, it is often used off-label in AML treatment, most notably after HSCT, in numerous sites [61]. ...
... Gilteritinib is a second-generation type 1 tyrosine kinase inhibitor (TKI) that primarily targets FLT3 and AXL (an oncogenic tyrosine kinase) receptors [61,76]. In September 2018, it was approved in Japan for the treatment of R/R FLT3-mutated AML, and 2 months later, it was approved in the same indications by the FDA [76]. ...
Acute myeloid leukemia (AML) is a disease that mainly affects elderly patients who are more often unfit for intensive chemotherapy (median age of diagnosis is 68). The regimens, including venetoclax, a highly specific BCL-2 (B-cell lymphoma-2) inhibitor, are a common alternative because of their safer profile and fewer side effects. However, the resistance phenomenon of leukemic cells necessitates the search for drugs that would help to overcome the resistance and improve treatment outcomes. One of the resistance mechanisms takes place through the upregulation of MCL-1 and BCL-XL, preventing BAX/BAK-driven MOMP (mitochondrial outer membrane permeabilization), thus stopping the apoptosis process. Possible partners for BCL-2 inhibitors may include inhibitors from the FLT3i (FMS-like tyrosine kinase-3 inhibitor) group. They resensitize cancer cells through the downregulation of MCL-1 expression in the FLT3 mutated cells, resulting in the stronger efficacy of BCL-2 inhibitors. Also, they provide an additional pathway for targeting the clonal cell. Both preclinical and clinical data suggest that the combination might show a synergistic effect and improve patients’ outcomes. The aim of this review is to determine whether the combination of venetoclax and FLT3 inhibitors can impact the therapeutic approaches and what other agents they can be combined with.
... FMS-related tyrosine kinase 3 (FLT3) mutations are detected in approximately 25-30% of acute myeloid leukemia (AML) patients, thus representing one of the most frequent mutations in AML [1]. Binding of FLT3 ligand (FLT3L) to FLT3 activates the phosphatidylinositol 3-kinase (PI3K) and RAS pathways, producing increased cell proliferation and inhibiting apoptosis [2]. Gilteritinib is currently the only FLT3 inhibitor approved for patients with relapsed or refractory (R/R) AML [3], based on the positive results of the pivotal ADMIRAL study: the median overall survival (OS) was significantly longer in patients treated with gilteritinib than among patients receiving any type of chemotherapy (9.3 vs. 5.6 months) [4]. ...
Gilteritinib is currently approved for patients with relapsed/refractory AML with FLT3 mutations, based on the positive results of the pivotal ADMIRAL study. In ADMIRAL trial, no increased risk of bleeding was reported, but in the previous dose finding study, a single event of intracranial hemorrhage (ICH) was registered after exposure to subtherapeutic doses of gilteritinib. Here we report the first case series on five early ICHs diagnosed in patients with FLT3-mutated AML, within the first month of exposure to gilteritinib. Our cohort included 24 patients treated in three Italian centers. Most of these ICH cases were non-severe and self-limiting, while one was fatal. This link with ICHs remains in any case uncertain for the presence of active AML. We further note that an analysis of the Postmarketing Surveillance Data (EudraVigilance), retrieved other 11 cases of ICHs present in the database after gilteritinib treatment. A causality assessment was performed according to the Dx3 method to evaluate the possibility that ICHs might be an actual side effect of gilteritinib. In conclusion, further research is needed to elucidate the potential role of gilteritinib in the pathogenesis of ICHs.
FLT3 internal tandem duplication (FLT3-ITD) mutations are one of the most prevalent somatic alterations associated with poor prognosis in patients with acute myeloid leukemia (AML). The clinically approved FLT3 kinase inhibitors gilteritinib and quizartinib improve the survival of patients with AML with FLT3-ITD mutations, but their long-term efficacy is limited by acquisition of secondary drug-resistant mutations. In this study, we conducted virtual screening of a library of 60,411 small molecules and identified foretinib as a potent FLT3 inhibitor. An integrated analysis of the BeatAML database showed that foretinib had a lower IC50 value than other existing FLT3 inhibitors in patients with FLT3-ITD AML. Foretinib directly bound to FLT3 and effectively inhibited FLT3 signaling. Foretinib potently inhibited proliferation and promoted apoptosis in human AML cell lines and primary AML cells with FLT3-ITD mutations. Foretinib also significantly extended the survival of mice bearing cell-derived and patient-derived FLT3-ITD xenografts, exhibiting stronger efficacy than clinically approved FLT3 inhibitors in treating FLT3-ITD AML. Moreover, foretinib showed potent activity against secondary mutations of FLT3-ITD that confer resistance to quizartinib and gilteritinib. These findings support the potential of foretinib for treating patients with AML with FLT3-ITD mutations, especially for those carrying secondary mutations after treatment failure with other FLT3 inhibitors.
Significance
Foretinib exhibits superior efficacy to approved drugs in AML with FLT3-ITD mutations and retains activity in AML with secondary FLT3 mutations that mediate resistance to clinical FLT3 inhibitors.
