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

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

doi:10.1038/s41375-023-02086-6

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

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

Research output: Contribution to journal › Article › peer-review

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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. [Figure not available: see fulltext.].

Original language	English (US)
Journal	Leukemia
DOIs	https://doi.org/10.1038/s41375-023-02086-6
State	Accepted/In press - 2023

ASJC Scopus subject areas

Hematology
Oncology
Cancer Research

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Tyagi, A., Jaggupilli, A., Ly, S., Yuan, B., El-Dana, F., Hegde, V., Anand, V., Kumar, B., Puppala, M., Yin, Z., Wong, S. T. C., Mollard, A., Vankayalapati, H., Foulks, J. M., Warner, S. L., Daver, N., Borthakur, G., & Battula, V. L. (Accepted/In press). TP-0184 inhibits FLT3/ACVR1 to overcome FLT3 inhibitor resistance and hinder AML growth synergistically with venetoclax. Leukemia. https://doi.org/10.1038/s41375-023-02086-6

Tyagi, A, Jaggupilli, A, Ly, S, Yuan, B, El-Dana, F, Hegde, V, Anand, V, Kumar, B, Puppala, M, Yin, Z, Wong, STC, Mollard, A, Vankayalapati, H, Foulks, JM, Warner, SL, Daver, N , Borthakur, G & Battula, VL 2023, 'TP-0184 inhibits FLT3/ACVR1 to overcome FLT3 inhibitor resistance and hinder AML growth synergistically with venetoclax', Leukemia. https://doi.org/10.1038/s41375-023-02086-6

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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. [Figure not available: see fulltext.].",

author = "Anudishi Tyagi and Appalaraju Jaggupilli and Stanley Ly and Bin Yuan and Fouad El-Dana and Venkatesh Hegde 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 = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2023",

doi = "10.1038/s41375-023-02086-6",

language = "English (US)",

journal = "Leukemia",

issn = "0887-6924",

publisher = "Springer Nature",

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T1 - TP-0184 inhibits FLT3/ACVR1 to overcome FLT3 inhibitor resistance and hinder AML growth synergistically with venetoclax

AU - Tyagi, Anudishi

AU - Jaggupilli, Appalaraju

AU - Ly, Stanley

AU - Yuan, Bin

AU - El-Dana, Fouad

AU - Hegde, Venkatesh

AU - Anand, Vivek

AU - Kumar, Bijender

AU - Puppala, Mamta

AU - Yin, Zheng

AU - Wong, Stephen T.C.

AU - Mollard, Alexis

AU - Vankayalapati, Hariprasad

AU - Foulks, Jason M.

AU - Warner, Steven L.

AU - Daver, Naval

AU - Borthakur, Gautam

AU - Battula, V. Lokesh

PY - 2023

Y1 - 2023

N2 - 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. [Figure not available: see fulltext.].

AB - 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. [Figure not available: see fulltext.].

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AN - SCOPUS:85178158867

SN - 0887-6924

JO - Leukemia

JF - Leukemia

ER -

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

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ASJC Scopus subject areas

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