Reference Detail

Ref Type

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	Vol	Issue	Date	Pages	Journal Short Title
Journal of hematology & oncology	14	1	2021 Jul 03	105	J Hematol Oncol

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
KX2-391	KX2-391	10	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
KX2-391		KX-01\|Tirbanibulin	FLT3 Inhibitor 69 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 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 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 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 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
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