Reference Detail

Ref Type

Journal Article

PMID

(38007585)

Authors

Tyagi A, Jaggupilli A, Ly S, Yuan B, El-Dana F, Hegde VL, Anand V, Kumar B, Puppala M, Yin Z, Wong STC, Mollard A, Vankayalapati H, Foulks JM, Warner SL, Daver N, Borthakur G, Battula VL

Title

TP-0184 inhibits FLT3/ACVR1 to overcome FLT3 inhibitor resistance and hinder AML growth synergistically with venetoclax.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Leukemia			2023 Nov 25		Leukemia

URL

Abstract Text

We identified activin A receptor type I (ACVR1), a member of the TGF-β superfamily, as a factor favoring acute myeloid leukemia (AML) growth and a new potential therapeutic target. ACVR1 is overexpressed in FLT3-mutated AML and inhibition of ACVR1 expression sensitized AML cells to FLT3 inhibitors. We developed a novel ACVR1 inhibitor, TP-0184, which selectively caused growth arrest in FLT3-mutated AML cell lines. Molecular docking and in vitro kinase assays revealed that TP-0184 binds to both ACVR1 and FLT3 with high affinity and inhibits FLT3/ACVR1 downstream signaling. Treatment with TP-0184 or in combination with BCL2 inhibitor, venetoclax dramatically inhibited leukemia growth in FLT3-mutated AML cell lines and patient-derived xenograft models in a dose-dependent manner. These findings suggest that ACVR1 is a novel biomarker and plays a role in AML resistance to FLT3 inhibitors and that FLT3/ACVR1 dual inhibitor TP-0184 is a novel potential therapeutic tool for AML with FLT3 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
TP-0184	TP-0184	1	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
TP-0184		TP0184\|TP 0184\|itacnosertib	FLT3 Inhibitor 66	TP-0184 inhibits ACVR1 and FLT3 and reduces downstream signaling, potentially resulting in decreased tumor cell proliferation and inhibition of tumor growth (PMID: 38007585).

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	acute myeloid leukemia	sensitive	TP-0184 + Venetoclax	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of TP-0184 and Venclexta (venetoclax) synergistically inhibited proliferation of acute myeloid leukemia cells harboring a FLT3-ITD in culture, and inhibited tumor growth and prolonged survival in a cell line xenograft model (PMID: 38007585).	38007585
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	TP-0184	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, TP-0184 inhibited proliferation and growth of acute myeloid leukemia cells harboring a FLT3-ITD mutation in culture, and inhibited tumor growth and improved survival in cell line and patient-derived xenograft models (PMID: 38007585).	38007585