Tyagi Anudishi, Jaggupilli Appalaraju, Ly Stanley, Yuan Bin, El-Dana Fouad, Hegde Venkatesh L, Anand Vivek, Kumar Bijender, Puppala Mamta, Yin Zheng, Wong Stephen T C, Mollard Alexis, Vankayalapati Hariprasad, Foulks Jason M, Warner Steven L, Daver Naval, Borthakur Gautam, Battula V Lokesh
Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Leukemia. 2024 Jan;38(1):82-95. doi: 10.1038/s41375-023-02086-6. Epub 2023 Nov 25.
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.
我们鉴定出转化生长因子-β（TGF-β）超家族成员激活素A受体I型（ACVR1）是一种促进急性髓系白血病（AML）生长的因子及一个新的潜在治疗靶点。ACVR1在FLT3突变的AML中过表达，抑制ACVR1表达可使AML细胞对FLT3抑制剂敏感。我们开发了一种新型ACVR1抑制剂TP-0184，它能选择性地使FLT3突变的AML细胞系生长停滞。分子对接和体外激酶试验表明，TP-0184以高亲和力与ACVR1和FLT3结合，并抑制FLT3/ACVR1下游信号传导。用TP-0184治疗或与BCL2抑制剂维奈托克联合使用，可显著抑制FLT-3突变的AML细胞系和患者来源异种移植模型中的白血病生长，且呈剂量依赖性。这些发现表明，ACVR1是一种新型生物标志物，在AML对FLT3抑制剂的耐药中起作用，并且FLT3/ACVR·1双重抑制剂TP-0184是一种用于治疗FLT3突变AML的新型潜在治疗工具。
Zotero 插件