AXL/MERTK inhibitor ONO-7475 potently synergizes with venetoclax and overcomes venetoclax resistance to kill FLT3-ITD acute myeloid leukemia

Sean M. Post; Huaxian Ma; Prerna Malaney; Xiaorui Zhang; Marisa J.L. Aitken; Po Yee Mak; Vivian R. Ruvolo; Tomoko Yasuhiro; Ryohei Kozaki; Lauren E. Chan; Lauren B. Ostermann; Marina Konopleva; Bing Z. Carter; Courtney DiNardo; Michael D. Andreeff; Joseph D. Khoury; Peter P. Ruvolo

doi:10.3324/haematol.2021.278369

AXL/MERTK inhibitor ONO-7475 potently synergizes with venetoclax and overcomes venetoclax resistance to kill FLT3-ITD acute myeloid leukemia

Sean M. Post, Huaxian Ma, Prerna Malaney, Xiaorui Zhang, Marisa J.L. Aitken, Po Yee Mak, Vivian R. Ruvolo, Tomoko Yasuhiro, Ryohei Kozaki, Lauren E. Chan, Lauren B. Ostermann, Marina Konopleva, Bing Z. Carter, Courtney DiNardo, Michael D. Andreeff, Joseph D. Khoury, Peter P. Ruvolo

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

24 Scopus citations

Abstract

FMS-like Tyrosine Kinase 3 (FLT3) mutation is associated with poor survival in acute myeloid leukemia (AML). The specific Anexelekto/MER Tyrosine Kinase (AXL) inhibitor, ONO-7475, kills FLT3-mutant AML cells with targets including Extracellular-signal Regulated Kinase (ERK) and Myeloid Cell Leukemia 1 (MCL1). ERK and MCL1 are known resistance factors for Venetoclax (ABT-199), a popular drug for AML therapy, prompting the investigation of the efficacy of ONO-7475 in combination with ABT-199 in vitro and in vivo. ONO-7475 synergizes with ABT-199 to potently kill FLT3-mutant acute myeloid leukemia cell lines and primary cells. ONO-7475 is effective against ABT-199-resistant cells including cells that overexpress MCL1. Proteomic analyses revealed that ABT-199-resistant cells expressed elevated levels of pro-growth and anti-apoptotic proteins compared to parental cells, and that ONO-7475 reduced the expression of these proteins in both the parental and ABT-199-resistant cells. ONO-7475 treatment significantly extended survival as a single in vivo agent using acute myeloid leukemia cell lines and PDX models. Compared to ONO-7474 monotherapy, the combination of ONO-7475/ABT-199 was even more potent in reducing leukemic burden and prolonging the survival of mice in both model systems. These results suggest that the ONO-7475/ABT-199 combination may be effective for AML therapy.

Original language	English (US)
Pages (from-to)	1311-1322
Number of pages	12
Journal	Haematologica
Volume	107
Issue number	6
DOIs	https://doi.org/10.3324/haematol.2021.278369
State	Published - Jun 2022
Externally published	Yes

ASJC Scopus subject areas

Hematology

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10.3324/haematol.2021.278369

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Post, S. M., Ma, H., Malaney, P., Zhang, X., Aitken, M. J. L., Mak, P. Y., Ruvolo, V. R., Yasuhiro, T., Kozaki, R., Chan, L. E., Ostermann, L. B., Konopleva, M., Carter, B. Z., DiNardo, C., Andreeff, M. D., Khoury, J. D., & Ruvolo, P. P. (2022). AXL/MERTK inhibitor ONO-7475 potently synergizes with venetoclax and overcomes venetoclax resistance to kill FLT3-ITD acute myeloid leukemia. Haematologica, 107(6), 1311-1322. https://doi.org/10.3324/haematol.2021.278369

Post, SM, Ma, H, Malaney, P, Zhang, X, Aitken, MJL, Mak, PY, Ruvolo, VR, Yasuhiro, T, Kozaki, R, Chan, LE, Ostermann, LB, Konopleva, M, Carter, BZ, DiNardo, C, Andreeff, MD, Khoury, JD & Ruvolo, PP 2022, 'AXL/MERTK inhibitor ONO-7475 potently synergizes with venetoclax and overcomes venetoclax resistance to kill FLT3-ITD acute myeloid leukemia', Haematologica, vol. 107, no. 6, pp. 1311-1322. https://doi.org/10.3324/haematol.2021.278369

@article{e5c749da5b4849e7accf7b415a9dbebe,

title = "AXL/MERTK inhibitor ONO-7475 potently synergizes with venetoclax and overcomes venetoclax resistance to kill FLT3-ITD acute myeloid leukemia",

abstract = "FMS-like Tyrosine Kinase 3 (FLT3) mutation is associated with poor survival in acute myeloid leukemia (AML). The specific Anexelekto/MER Tyrosine Kinase (AXL) inhibitor, ONO-7475, kills FLT3-mutant AML cells with targets including Extracellular-signal Regulated Kinase (ERK) and Myeloid Cell Leukemia 1 (MCL1). ERK and MCL1 are known resistance factors for Venetoclax (ABT-199), a popular drug for AML therapy, prompting the investigation of the efficacy of ONO-7475 in combination with ABT-199 in vitro and in vivo. ONO-7475 synergizes with ABT-199 to potently kill FLT3-mutant acute myeloid leukemia cell lines and primary cells. ONO-7475 is effective against ABT-199-resistant cells including cells that overexpress MCL1. Proteomic analyses revealed that ABT-199-resistant cells expressed elevated levels of pro-growth and anti-apoptotic proteins compared to parental cells, and that ONO-7475 reduced the expression of these proteins in both the parental and ABT-199-resistant cells. ONO-7475 treatment significantly extended survival as a single in vivo agent using acute myeloid leukemia cell lines and PDX models. Compared to ONO-7474 monotherapy, the combination of ONO-7475/ABT-199 was even more potent in reducing leukemic burden and prolonging the survival of mice in both model systems. These results suggest that the ONO-7475/ABT-199 combination may be effective for AML therapy.",

author = "Post, {Sean M.} and Huaxian Ma and Prerna Malaney and Xiaorui Zhang and Aitken, {Marisa J.L.} and Mak, {Po Yee} and Ruvolo, {Vivian R.} and Tomoko Yasuhiro and Ryohei Kozaki and Chan, {Lauren E.} and Ostermann, {Lauren B.} and Marina Konopleva and Carter, {Bing Z.} and Courtney DiNardo and Andreeff, {Michael D.} and Khoury, {Joseph D.} and Ruvolo, {Peter P.}",

note = "Publisher Copyright: {\textcopyright}2022 Ferrata Storti Foundation",

year = "2022",

month = jun,

doi = "10.3324/haematol.2021.278369",

language = "English (US)",

volume = "107",

pages = "1311--1322",

journal = "Haematologica",

issn = "0390-6078",

publisher = "Ferrata Storti Foundation",

number = "6",

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T1 - AXL/MERTK inhibitor ONO-7475 potently synergizes with venetoclax and overcomes venetoclax resistance to kill FLT3-ITD acute myeloid leukemia

AU - Post, Sean M.

AU - Ma, Huaxian

AU - Malaney, Prerna

AU - Zhang, Xiaorui

AU - Aitken, Marisa J.L.

AU - Mak, Po Yee

AU - Ruvolo, Vivian R.

AU - Yasuhiro, Tomoko

AU - Kozaki, Ryohei

AU - Chan, Lauren E.

AU - Ostermann, Lauren B.

AU - Konopleva, Marina

AU - Carter, Bing Z.

AU - DiNardo, Courtney

AU - Andreeff, Michael D.

AU - Khoury, Joseph D.

AU - Ruvolo, Peter P.

PY - 2022/6

Y1 - 2022/6

N2 - FMS-like Tyrosine Kinase 3 (FLT3) mutation is associated with poor survival in acute myeloid leukemia (AML). The specific Anexelekto/MER Tyrosine Kinase (AXL) inhibitor, ONO-7475, kills FLT3-mutant AML cells with targets including Extracellular-signal Regulated Kinase (ERK) and Myeloid Cell Leukemia 1 (MCL1). ERK and MCL1 are known resistance factors for Venetoclax (ABT-199), a popular drug for AML therapy, prompting the investigation of the efficacy of ONO-7475 in combination with ABT-199 in vitro and in vivo. ONO-7475 synergizes with ABT-199 to potently kill FLT3-mutant acute myeloid leukemia cell lines and primary cells. ONO-7475 is effective against ABT-199-resistant cells including cells that overexpress MCL1. Proteomic analyses revealed that ABT-199-resistant cells expressed elevated levels of pro-growth and anti-apoptotic proteins compared to parental cells, and that ONO-7475 reduced the expression of these proteins in both the parental and ABT-199-resistant cells. ONO-7475 treatment significantly extended survival as a single in vivo agent using acute myeloid leukemia cell lines and PDX models. Compared to ONO-7474 monotherapy, the combination of ONO-7475/ABT-199 was even more potent in reducing leukemic burden and prolonging the survival of mice in both model systems. These results suggest that the ONO-7475/ABT-199 combination may be effective for AML therapy.

AB - FMS-like Tyrosine Kinase 3 (FLT3) mutation is associated with poor survival in acute myeloid leukemia (AML). The specific Anexelekto/MER Tyrosine Kinase (AXL) inhibitor, ONO-7475, kills FLT3-mutant AML cells with targets including Extracellular-signal Regulated Kinase (ERK) and Myeloid Cell Leukemia 1 (MCL1). ERK and MCL1 are known resistance factors for Venetoclax (ABT-199), a popular drug for AML therapy, prompting the investigation of the efficacy of ONO-7475 in combination with ABT-199 in vitro and in vivo. ONO-7475 synergizes with ABT-199 to potently kill FLT3-mutant acute myeloid leukemia cell lines and primary cells. ONO-7475 is effective against ABT-199-resistant cells including cells that overexpress MCL1. Proteomic analyses revealed that ABT-199-resistant cells expressed elevated levels of pro-growth and anti-apoptotic proteins compared to parental cells, and that ONO-7475 reduced the expression of these proteins in both the parental and ABT-199-resistant cells. ONO-7475 treatment significantly extended survival as a single in vivo agent using acute myeloid leukemia cell lines and PDX models. Compared to ONO-7474 monotherapy, the combination of ONO-7475/ABT-199 was even more potent in reducing leukemic burden and prolonging the survival of mice in both model systems. These results suggest that the ONO-7475/ABT-199 combination may be effective for AML therapy.

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AXL/MERTK inhibitor ONO-7475 potently synergizes with venetoclax and overcomes venetoclax resistance to kill FLT3-ITD acute myeloid leukemia

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