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Ref Type Journal Article
PMID (34768286)
Authors Azhar M, Kincaid Z, Kesarwani M, Ahmed A, Wunderlich M, Latif T, Starczynowski D, Azam M
Title Momelotinib is a highly potent inhibitor of FLT3-mutant AML.
Journal Vol Issue Date Pages Journal Short Title
Blood advances 6 4 2022 Feb 22 1186-1192 Blood Adv
URL
Abstract Text Despite the introduction of more selective FLT3 inhibitors to treat FLT3-mutated acute myeloid leukemia (AML), remissions are short lived, and patients show progressive disease after an initial response. Acquisition of resistance-conferring genetic mutations and growth factor signaling are 2 principal mechanisms that drive relapse. FLT3 inhibitors targeting both escape mechanisms could lead to a more profound and lasting clinical response. Here, we show that the JAK2 inhibitor momelotinib is an equipotent type 1 FLT3 inhibitor. Momelotinib showed potent inhibition of FLT3-internal tandem duplication in mouse and human primary cells and effectively suppressed its clinically relevant resistant variants within the activation loop at residues D835, D839, and Y842. Additionally, momelotinib efficiently suppressed the resistance mediated by growth factors and hematopoietic cytokine-activated JAK2 signaling. Consequently, concomitant inhibition of FLT3 and suppression of growth factor signaling by momelotinib treatment showed better efficacy in suppressing leukemia in a preclinical murine model of AML. Altogether, these data provide evidence that momelotinib is an effective type 1 dual JAK2/FLT3 inhibitor and may offer an alternative to gilteritinib. Its ability to impede the resistance conferred by growth factor signaling and activation loop mutants suggests that momelotinib treatment could provide a deeper and durable response and, thus, warrants its clinical evaluation.

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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
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 F691L hematologic cancer resistant Sorafenib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD and FLT3 F691L demonstrated resistance to Nexavar (sorafenib) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 D835V hematologic cancer resistant Pacritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD and FLT3 D835V demonstrated resistance to Vonjo (pacritinib) in culture (PMID: 34768286). 34768286
JAK2 V617F hematologic cancer sensitive Momelotinib Preclinical - Cell culture Actionable In a preclinical study, Momelotinib (CYT387) inhibited proliferation of transformed cells expressing JAK2 V617F in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 D839G hematologic cancer sensitive Momelotinib Preclinical - Cell culture Actionable In a preclinical study, Momelotinib (CYT387) decreased phosphorylation of Flt3 and Stat5 and inhibited proliferation of transformed cells expressing FLT3-ITD and FLT3 D839G in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 F691L FLT3 D835Y hematologic cancer resistant Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD, FLT3 F691L, and FLT3 D835Y demonstrated resistance to Xospata (gilteritinib) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 D835V hematologic cancer sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, transformed hematologic cells expressing FLT3-ITD and FLT3 D835V were sensitive to Crenolanib (CP-868596) treatment in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 F691L FLT3 Y842H hematologic cancer resistant Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD, FLT3 F691L, and FLT3 Y842H demonstrated resistance to Xospata (gilteritinib) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 F691L FLT3 D835Y hematologic cancer resistant Pacritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD, FLT3 F691L, and FLT3 D835Y demonstrated resistance to Vonjo (pacritinib) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 F691L FLT3 Y842H hematologic cancer resistant Sorafenib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD, FLT3 F691L, and FLT3 Y842H demonstrated resistance to Nexavar (sorafenib) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 F691L FLT3 Y842H hematologic cancer resistant Quizartinib Preclinical - Cell culture Actionable In a preclinical study, transformed hematologic cells expressing FLT3-ITD, FLT3 F691L, and FLT3 Y842H demonstrated resistance to Vanflyta (quizartinib) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 D835Y hematologic cancer sensitive Momelotinib Preclinical - Cell culture Actionable In a preclinical study, Momelotinib (CYT387) decreased phosphorylation of Flt3 and Stat5 and inhibited proliferation of transformed cells expressing FLT3-ITD and FLT3 D835Y in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 D839G hematologic cancer resistant Sorafenib Preclinical - Biochemical Actionable In a preclinical study, transformed cells expressing FLT3-ITD and FLT3 D839G demonstrated resistance to Nexavar (sorafenib) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 D835Y hematologic cancer sensitive Midostaurin Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD and FLT3 D835Y were sensitive to Rydapt (midostaurin) treatment in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 F691L FLT3 Y842H hematologic cancer resistant Crenolanib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD, FLT3 F691L, and FLT3 Y842H demonstrated resistance to Crenolanib (CP-868596) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 Y842H hematologic cancer resistant Sorafenib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD and FLT3 Y842H demonstrated resistance to Nexavar (sorafenib) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 D835V hematologic cancer resistant Sorafenib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD and FLT3 D835V demonstrated resistance to Nexavar (sorafenib) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 F691L FLT3 D835Y hematologic cancer resistant Crenolanib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD, FLT3 F691L, and FLT3 D835Y demonstrated resistance to Crenolanib (CP-868596) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 D835Y hematologic cancer sensitive Lestaurtinib Preclinical - Cell culture Actionable In a preclinical study, Lestaurtinib (CEP-701) inhibited proliferation of transformed cells expressing FLT3-ITD and FLT3 D835Y in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 D835Y hematologic cancer conflicting Pacritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD and FLT3 D835Y demonstrated resistance to Vonjo (pacritinib) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 F691L hematologic cancer conflicting Pacritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD and FLT3 F691L demonstrated resistance to Vonjo (pacritinib) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 F691L FLT3 Y842H hematologic cancer resistant Pacritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD, FLT3 F691L, and FLT3 Y842H demonstrated resistance to Vonjo (pacritinib) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 Y842H hematologic cancer sensitive Momelotinib Preclinical - Cell culture Actionable In a preclinical study, Momelotinib (CYT387) decreased phosphorylation of Flt3 and Stat5 and inhibited proliferation of transformed cells expressing FLT3-ITD and FLT3 Y842H in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins hematologic cancer sensitive Momelotinib Preclinical - Cell culture Actionable In a preclinical study, Momelotinib (CYT387) decreased phosphorylation of Flt3 and Stat5 and inhibited proliferation of transformed cells expressing a FLT3-ITD mutation in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 D835Y hematologic cancer sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) inhibited proliferation of transformed cells expressing FLT3-ITD and FLT3 D835Y in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 F691L hematologic cancer predicted - resistant Crenolanib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD and FLT3 F691L, and FLT3 D835Y were resistant to Crenolanib (CP-868596) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 D835Y hematologic cancer resistant Sorafenib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD and FLT3 D835Y demonstrated resistance to Nexavar (sorafenib) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 D839G hematologic cancer sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) inhibited proliferation of transformed cells expressing FLT3-ITD and FLT3 D839G in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins acute myeloid leukemia sensitive Momelotinib Preclinical - Cell line xenograft Actionable In a preclinical study, Momelotinib (CYT387) inhibited proliferation of acute myeloid leukemia cell lines and patient-derived cells harboring FLT3-ITD mutations in culture, and resulted in prolonged survival and reduced leukemic burden in cell line xenograft models (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 F691L FLT3 D835Y hematologic cancer resistant Sorafenib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD, FLT3 F691L, and FLT3 D835Y demonstrated resistance to Nexavar (sorafenib) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 Y842H hematologic cancer resistant Pacritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD and FLT3 Y842H demonstrated resistance to Vonjo (pacritinib) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 D839G hematologic cancer sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, transformed hematologic cells expressing FLT3-ITD and FLT3 D839G were sensitive to Crenolanib (CP-868596) treatment in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 Y842H hematologic cancer sensitive Midostaurin Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD and FLT3 Y842H were sensitive to Rydapt (midostaurin) treatment in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 Y842H hematologic cancer sensitive Lestaurtinib Preclinical - Cell culture Actionable In a preclinical study, Lestaurtinib (CEP-701) inhibited proliferation of transformed cells expressing FLT3-ITD and FLT3 Y842H in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 F691L FLT3 D835Y hematologic cancer resistant Momelotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD with FLT3 F691L and D835Y demonstrated resistance to Momelotinib (CYT387) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 D835V hematologic cancer sensitive Midostaurin Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD and FLT3 D835V were sensitive to Rydapt (midostaurin) treatment in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 D835Y hematologic cancer sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, transformed hematologic cells expressing FLT3-ITD and FLT3 D835Y were sensitive to Crenolanib (CP-868596) treatment in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 D839G hematologic cancer sensitive Midostaurin Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD and FLT3 D839G were sensitive to Rydapt (midostaurin) treatment in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 Y842H hematologic cancer sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, transformed hematologic cells expressing FLT3-ITD and FLT3 Y842H were sensitive to Crenolanib (CP-868596) treatment in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 F691L FLT3 D835Y hematologic cancer resistant Quizartinib Preclinical - Cell culture Actionable In a preclinical study, transformed hematologic cells expressing FLT3-ITD, FLT3 F691L, and FLT3 D835Y demonstrated resistance to Vanflyta (quizartinib) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 F691L hematologic cancer resistant Lestaurtinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD and FLT3 F691L demonstrated resistance to Lestaurtinib (CEP-701) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 D835V hematologic cancer sensitive Lestaurtinib Preclinical - Cell culture Actionable In a preclinical study, Lestaurtinib (CEP-701) inhibited proliferation of transformed cells expressing FLT3-ITD and FLT3 D835V in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 D839G hematologic cancer sensitive Lestaurtinib Preclinical - Cell culture Actionable In a preclinical study, Lestaurtinib (CEP-701) inhibited proliferation of transformed cells expressing FLT3-ITD and FLT3 D839G in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 F691L hematologic cancer resistant Momelotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD and FLT3 F691L demonstrated resistance to Momelotinib (CYT387) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 D839G hematologic cancer resistant Pacritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD and FLT3 D839G demonstrated resistance to Vonjo (pacritinib) in culture (PMID: 34768286). 34768286
FLT3 exon 14 ins FLT3 Y842H hematologic cancer sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) inhibited proliferation of transformed cells expressing FLT3-ITD and FLT3 Y842H in culture (PMID: 34768286). 34768286