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PMID (34217323)
Authors Wang P, Xiao X, Zhang Y, Zhang B, Li D, Liu M, Xie X, Liu C, Liu P, Ren R
Title A dual inhibitor overcomes drug-resistant FLT3-ITD acute myeloid leukemia.
Journal Journal of hematology & oncology
Vol 14
Issue 1
Date 2021 Jul 03
URL
Abstract Text FLT3 mutations are the most frequently identified genetic alterations in acute myeloid leukemia (AML) and are associated with poor prognosis. Multiple FLT3 inhibitors are in various stages of clinical evaluation. However, resistance to FLT3 inhibitors resulting from acquired point mutations in tyrosine kinase domain (TKD) have limited the sustained efficacy of treatments, and a "gatekeeper" mutation (F691L) is resistant to most available FLT3 inhibitors. Thus, new FLT3 inhibitors against both FLT3 internal tandem duplication (FLT3-ITD) and FLT3-TKD mutations (including F691L) are urgently sought. Herein, we identified KX2-391 as a dual FLT3 and tubulin inhibitor and investigated its efficacy and mechanisms in overcoming drug-resistant FLT3-ITD-TKD mutations in AML. KX2-391 exhibited potent growth inhibitory and apoptosis promoting effects on diverse AML cell lines harboring FLT3-ITD mutations and AC220-resistant mutations at the D835 and F691 residues in TKD and inhibited FLT3 phosphorylation and its downstream signaling targets. Orally administered KX2-391 significantly prolonged the survival of a murine leukemia model induced by FLT3-ITD-F691L. KX2-391 also significantly inhibited the growth of 4 primary AML cells expressing FLT3-ITD and 2 primary AML cells expressing FLT3-ITD-D835Y. Our preclinical data highlight KX2-391 as a promising FLT3 inhibitor for the treatment of AML patients harboring FLT3 mutations, especially refractory/relapsed patients with F691L and other FLT3-TKD mutations.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
KX2-391 KX-01|Tirbanibulin FLT3 Inhibitor 61 SRC Inhibitor 31 Tirbanibulin (KX2-391) is a peptidomimetic inhibitor of Src and pretubulin, with additional activity against FLT3, potentially resulting in decreased tumor growth and metastasis (PMID: 22784709, PMID: 31628188, PMID: 34217323).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FLT3 exon 14 ins FLT3 D835V hematologic cancer sensitive KX2-391 Preclinical - Cell culture Actionable In a preclinical study, KX2-391 treatment inhibited cell viability and decreased downstream signaling in cells expressing a FLT3-ITD mutation with FLT3 D835V in culture (PMID: 34217323). 34217323
FLT3 exon 14 ins FLT3 D835F hematologic cancer sensitive KX2-391 Preclinical - Cell culture Actionable In a preclinical study, KX2-391 treatment inhibited cell viability and decreased downstream signaling in cells expressing a FLT3-ITD mutation with FLT3 D835F in culture (PMID: 34217323). 34217323
FLT3 exon 14 ins FLT3 D835Y hematologic cancer sensitive KX2-391 Preclinical - Cell culture Actionable In a preclinical study, KX2-391 treatment inhibited cell viability, decreased downstream signaling, and induced apoptosis in cells expressing a FLT3-ITD mutation with FLT3 D835Y in culture (PMID: 34217323). 34217323
FLT3 exon 14 ins acute myeloid leukemia sensitive KX2-391 Preclinical - Patient cell culture Actionable In a preclinical study, KX2-391 treatment inhibited cell viability and decreased downstream signaling in acute myeloid leukemia cell lines and patient-derived cells harboring a FLT3-ITD mutation in culture (PMID: 34217323). 34217323
FLT3 exon 14 ins FLT3 F691L hematologic cancer sensitive KX2-391 Preclinical Actionable In a preclinical study, KX2-391 treatment inhibited viability, decreased downstream signaling, and induced apoptosis in cells expressing a FLT3-ITD mutation with FLT3 F691L in culture, and inhibited tumor growth and prolonged survival in mouse models (PMID: 34217323). 34217323
FLT3 exon 14 ins hematologic cancer sensitive KX2-391 Preclinical - Cell culture Actionable In a preclinical study, KX2-391 treatment inhibited cell viability, decreased downstream signaling, and induced apoptosis in cells expressing a FLT3-ITD mutation in culture (PMID: 34217323). 34217323
FLT3 exon 14 ins FLT3 D835Y acute myeloid leukemia predicted - sensitive KX2-391 Preclinical - Patient cell culture Actionable In a preclinical study, KX2-391 treatment inhibited cell viability and decreased Flt3 phosphorylation in patient-derived acute myeloid leukemia cell lines harboring a FLT3-ITD mutation with FLT3 D835Y in culture (PMID: 34217323). 34217323