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ACUTE MYELOID LEUKEMIA

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

Leukemia volume 38, pages 82–95 (2024)Cite this article

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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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Fig. 1: ACVR1 mRNA is overexpressed in AML patients with FLT3-ITD mutations, and its expression is further enhanced by FLT3 inhibitors.
Fig. 2: ACVR1 knockdown sensitizes FLT3-ITD–mutated AML cells to FLT3 inhibitors.
Fig. 3: TP-0184 inhibits cell proliferation in FLT3-mutated AML cells and interacts strongly with FLT3.
Fig. 4: TP-0184 inhibits FLT3- and ACVR1-mediated downstream signaling pathways in FLT3-ITD–mutated AML.
Fig. 5: TP-0184 inhibits serine biosynthesis in FLT3-mutated AML cells.
Fig. 6: TP-0184 inhibits leukemia growth in FLT3-ITD–mutated AML cell line xenograft and PDX models.
Fig. 7: TP-0184 and venetoclax synergistically inhibit the proliferation of FLT3-ITD–mutated cell lines and leukemia growth in vivo.

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Data availability

RNA-seq data is deposited in NCBI’s Gene Expression Omnibus (GEO) and are accessible through GEO series accession code GSE228427. Publicly available datasets, 2 datasets from TCGA and 1 dataset from OHSU, are available in cBioPortal.org. All of the data supporting the findings of this study are available from the corresponding author on reasonable request.

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Acknowledgements

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.

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  1. Deceased: Mamta Puppala.

Authors and Affiliations

  1. Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Anudishi Tyagi, Appalaraju Jaggupilli, Stanley Ly, Bin Yuan, Fouad El-Dana, Venkatesh L. Hegde, Vivek Anand, Naval Daver, Gautam Borthakur & V. Lokesh Battula

  2. Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Bijender Kumar

  3. Department of Systems Medicine and Bioengineering, Houston Methodist Neal Cancer Center, Weill Cornell Medicine, Houston, TX, USA

    Mamta Puppala, Zheng Yin & Stephen T. C. Wong

  4. University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA

    Alexis Mollard & Hariprasad Vankayalapati

  5. Sumitomo Pharma Oncology, Inc, Lehi, UT, USA

    Jason M. Foulks & Steven L. Warner

  6. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    V. Lokesh Battula

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Contributions

AT conducted experiments, analyzed the data, and wrote the manuscript. AJ performed all the docking studies. SL, BY, and FED conducted experiments and performed data analysis. VLH analyzed the data and contributed to manuscript preparation. VA and BK performed Western blotting experiments and analyzed the data. MP, YZ, and STCW. analyzed RNA-seq data using bioinformatics tools. JMF and SLW developed TP-0184 and tested its effect on ACVR1 kinase activity. AS compiled all the information on the discovery and development of TP-0184. ND, and GB contributed to conceptualization of the project and data analysis. VLB conceptualized the study, planned all the experiments, interpreted the results, edited the manuscript, and performed critical review of the intellectual content of the manuscript.

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Correspondence to V. Lokesh Battula.

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This work was supported by funding from Sumitomo Pharma Oncology and MD Anderson Cancer Center.

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Tyagi, A., Jaggupilli, A., Ly, S. et al. TP-0184 inhibits FLT3/ACVR1 to overcome FLT3 inhibitor resistance and hinder AML growth synergistically with venetoclax. Leukemia 38, 82–95 (2024). https://doi.org/10.1038/s41375-023-02086-6

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