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

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

  • Leukemia. 2024 Jan;38(1):82-95. doi: 10.1038/s41375-023-02086-6.
Anudishi Tyagi 1,  Appalaraju Jaggupilli 1,  Stanley Ly 1,  Bin Yuan 1,  Fouad El-Dana 1,  Venkatesh L Hegde 1,  Vivek Anand 1,  Bijender Kumar 2,  Mamta Puppala 3,  Zheng Yin 3,  Stephen T C Wong 3,  Alexis Mollard 4,  Hariprasad Vankayalapati 4,  Jason M Foulks 5,  Steven L Warner 5,  Naval Daver 1,  Gautam Borthakur 1,  V Lokesh Battula 6 7
Affiliations

Affiliations

  • 1 Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2 Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3 Department of Systems Medicine and Bioengineering, Houston Methodist Neal Cancer Center, Weill Cornell Medicine, Houston, TX, USA.
  • 4 University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA.
  • 5 Sumitomo Pharma Oncology, Inc, Lehi, UT, USA.
  • 6 Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. vbattula@mdanderson.org.
  • 7 Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. vbattula@mdanderson.org.
PMID: 38007585 DOI: 10.1038/s41375-023-02086-6
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.

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