Missing content? – Request curation!
Request curation for specific Genes, Variants, or PubMed publications.
Have questions, comments, or suggestions? - Let us know!
Email us at : ckbsupport@genomenon.com
| Ref Type | Journal Article | ||||||||||||
| PMID | (42035942) | ||||||||||||
| Authors | Gu C, He J, Fan J, Wang C, Zhou W, Xu Y, Deng T, Wang S, Wang P | ||||||||||||
| Title | Nintedanib is a potent FLT3 inhibitor with activity against FLT3-ITD and overcomes the gatekeeper F691L resistance mutation in acute myeloid leukemia. | ||||||||||||
|
|||||||||||||
| URL | |||||||||||||
| Abstract Text | Acute myeloid leukemia (AML) is a molecularly heterogeneous malignancy in which FMS-like tyrosine kinase 3 (FLT3) mutations, particularly internal tandem duplications (FLT3-ITD), occur in approximately 30% of cases and are associated with poor prognosis and high relapse risk. While FLT3 inhibitors have improved clinical outcomes, acquired resistance, often mediated by secondary tyrosine kinase domain (TKD) mutations or other mechanisms, remains a major therapeutic challenge. Nintedanib is an oral multi-kinase inhibitor approved for the treatment of fibrotic lung diseases; however, its potential activity against FLT3-ITD-positive AML has not been explored. Here, we identified nintedanib as a putative FLT3 inhibitor by analyzing drug-sensitivity data from the BeatAML database. Direct target engagement was validated by computational docking, cellular thermal shift assay (CETSA), and in vitro kinase inhibition assays. In FLT3-ITD-mutant human cell lines (MV4-11, MOLM13), primary AML blasts, and engineered Ba/F3 cells expressing FLT3-ITD with or without secondary TKD mutations, nintedanib suppressed FLT3 autophosphorylation and downstream STAT5, ERK, and AKT signaling, leading to cell cycle arrest and apoptosis. Notably, nintedanib retained efficacy against common resistance mutations, including the gatekeeper F691L mutation, both in vitro and in vivo. In a Ba/F3 FLT3-ITD-F691L mouse model, nintedanib demonstrated superior anti-leukemic efficacy compared with gilteritinib and quizartinib. Furthermore, nintedanib potently inhibited primary AML blasts harboring FLT3-ITD while normal bone marrow remained intact. These findings identify nintedanib as a promising FLT3 inhibitor and support its further therapeutic investigation in FLT3-ITD-positive AML. | ||||||||||||
| 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 | sensitive | Nintedanib | Preclinical | Actionable | In a preclinical study, Ofev (nintedanib) inhibited viability with greater potency compared to Nexavar (sorafenib) in cells expressing FLT3-ITD and FLT3 F691L in culture, and demonstrated enhanced suppression of tumor growth and longer survival compared to Xospata (gilteritinib) and Vanflyta (quizartinib) in mouse models (PMID: 42035942). | 42035942 |
| FLT3 exon 14 ins | acute myeloid leukemia | sensitive | Nintedanib | Preclinical - Cell culture | Actionable | In a preclinical study, Ofev (nintedanib) inhibited autophosphorylation and downstream signaling, induced cell cycle arrest and apoptosis and inhibited viability in acute myeloid cell lines harboring FLT3-ITD in culture (PMID: 42035942). | 42035942 |