@article{217115acddd74bd59eff41ccb12b80e2,
title = "TP-0184 inhibits FLT3/ACVR1 to overcome FLT3 inhibitor resistance and hinder AML growth synergistically with venetoclax",
abstract = "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.",
author = "Anudishi Tyagi and Appalaraju Jaggupilli and Stanley Ly and Bin Yuan and Fouad El-Dana and Hegde, {Venkatesh L} and Vivek Anand and Bijender Kumar and Mamta Puppala and Zheng Yin and Wong, {Stephen T C} and Alexis Mollard and Hariprasad Vankayalapati and Foulks, {Jason M} and Warner, {Steven L} and Naval Daver and Gautam Borthakur and Battula, {V Lokesh}",
note = "Funding Information: The authors thank the MD Anderson Flow Cytometry & Cellular Imaging Core Facility and Functional Genomics Core Facility, which are supported in part by The University of Texas MD Anderson Cancer Center and grant number P30CA016672 from the National Institutes of Health/National Cancer Institute. Thank to Dr. Adam Siddiqui for providing the information on the discovery and full characterisation of TP-0184. The authors also thank Amy Ninetto of the Research Medical Library at MD Anderson for editing the manuscript. Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2023",
month = nov,
day = "25",
doi = "10.1038/s41375-023-02086-6",
language = "English (US)",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",
}