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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. | ||||||||||||
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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 | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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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 | 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 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 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 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 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 |
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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 | 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 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 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 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 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 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 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 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 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 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 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 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 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 | 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 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 |
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 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 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 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 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 |
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 | 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 |
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