Reference Detail

Ref Type

Journal Article

PMID

(38978049)

Authors

Hu C, Zhang Y, Yang J, Xu Y, Deng T, Li Y, Xu S, Wang S, Wang P

Title

Ningetinib, a novel FLT3 inhibitor, overcomes secondary drug resistance in acute myeloid leukemia.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cell communication and signaling : CCS	22	1	2024 Jul 08	355	Cell Commun Signal

URL

Abstract Text

FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is a common mutation type in acute myeloid leukemia (AML) and is usually associated with poor patient prognosis. With advancements in molecular diagnostics and the development of tyrosine kinase inhibitors (TKI), the overall survival (OS) of AML patients with FLT3-ITD mutations has been prolonged to some extent, but relapse and drug resistance are still substantial challenges. Ningetinib is a novel TKI against various kinases in relation to tumour pathogenesis and is undergoing clinical trials of lung cancer. In this study, we explored the antitumor activity of ningetinib against AML with FLT3 mutations both in vivo and in vitro.Cell proliferation assays were performed in AML cell lines and Ba/F3 cells expressing various FLT3 mutations to validate the antileukemic activity of ningetinib in vitro. Immunoblot assays were used to verify the effect of ningetinib on the FLT3 protein and downstream pathways. Molecular docking and CETSA were used to validate the interaction of ningetinib with target proteins. The survival benefit of ningetinib in vivo was assessed in Ba/F3-FLT3-ITD-, MOLM13, Ba/F3-FLT3-ITD-F691L-, MOLM13-FLT3-ITD-F691L-induced leukemia mouse models. We also used patient-derived primary cells to determine the efficacy of ningetinib.Ningetinib inhibited cell proliferation, blocked the cell cycle, induced apoptosis and bound FLT3 to inhibit its downstream signaling pathways, including the STAT5, AKT and ERK pathways, in FLT3-ITD AML cell lines. In the mouse models with FLT3-ITD and FLT3-ITD-F691L mutation, ningetinib showed superior anti-leukemia activity to existing clinical drugs gilteritinib and quizartinib, significantly prolongating the survival of mice. In addition, ningetinib exhibited activity against patient-derived primary cells harboring FLT3-ITD mutations.Overall, our study confirmed the therapeutic role of ningetinib in AML with FLT3-ITD mutations, providing a potential new option for clinically resistant patients.

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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
Ningetinib	Ningetinib	8	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Ningetinib		CT053PTSA\|CT-053-PTSA	AXL Inhibitor 30 FLT3 Inhibitor 69 MET Inhibitor 59 VEGFR2 Inhibitor 37	Ningetinib (CT053PTSA) inhibits MET, VEGFR2, AXL, and FLT3, which potentially reduces tumor cell growth (PMID: 36341335, PMID: 38978049).

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	hematologic cancer	sensitive	Ningetinib	Preclinical	Actionable	In a preclinical study, Ningetinib (CT053PTSA) inhibited Flt3 downstream signaling and viability in a cell line expressing a FLT3-ITD in culture and decreased leukemic burden in a mouse model (PMID: 38978049).	38978049
FLT3 exon 14 ins FLT3 F691L	hematologic cancer	sensitive	Ningetinib	Preclinical	Actionable	In a preclinical study, Ningetinib (CT053PTSA) inhibited Flt3 downstream signaling and viability in a cell line expressing a FLT3-ITD and FLT3 F691L in culture and decreased leukemic burden and prolonged survival in a mouse model (PMID: 38978049).	38978049
FLT3 exon 14 ins FLT3 F691L	acute myeloid leukemia	sensitive	Ningetinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Ningetinib (CT053PTSA) decreased leukemic burden in a cell line xenograft model of acute myeloid leukemia harboring a FLT3-ITD and expressing FLT3 F691L (PMID: 38978049).	38978049
FLT3 exon 14 ins FLT3 D835Y	hematologic cancer	sensitive	Ningetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Ningetinib (CT053PTSA) inhibited Flt3 downstream signaling and viability in a cell line expressing a FLT3-ITD and FLT3 D835Y in culture (PMID: 38978049).	38978049
FLT3 exon 14 ins FLT3 N676D	hematologic cancer	sensitive	Ningetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Ningetinib (CT053PTSA) inhibited viability in a cell line expressing a FLT3-ITD and FLT3 N676D in culture (PMID: 38978049).	38978049
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Ningetinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Ningetinib (CT053PTSA) induced cell cycle arrest and apoptosis and inhibited Flt3 downstream signaling and viability in acute myeloid leukemia cell lines harboring a FLT3-ITD, inhibited Flt3 downstream signaling and proliferation in patient-derived cells in culture, and decreased leukemic burden in a cell line xenograft model (PMID: 38978049).	38978049
FLT3 exon 14 ins FLT3 Y842C	hematologic cancer	sensitive	Ningetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Ningetinib (CT053PTSA) inhibited Flt3 downstream signaling and viability in a cell line expressing a FLT3-ITD and FLT3 Y842C in culture (PMID: 38978049).	38978049
FLT3 exon 14 ins FLT3 D835V	hematologic cancer	sensitive	Ningetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Ningetinib (CT053PTSA) inhibited Flt3 downstream signaling and viability in a cell line expressing a FLT3-ITD and FLT3 D835V in culture (PMID: 38978049).	38978049