Article
作者: Wong, Stephen T C ; El-Dana, Fouad ; Battula, V Lokesh ; Borthakur, Gautam ; Foulks, Jason M ; Anand, Vivek ; Yuan, Bin ; Puppala, Mamta ; Yin, Zheng ; Kumar, Bijender ; Tyagi, Anudishi ; Warner, Steven L ; Daver, Naval ; Jaggupilli, Appalaraju ; Vankayalapati, Hariprasad ; Ly, Stanley ; Hegde, Venkatesh L ; Mollard, Alexis
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.