AXL/MERTK Inhibitor ONO-7475 Potently Synergizes With Venetoclax and Overcomes Venetoclax Resistance To Kill F LT 3-ITD Acute Myeloid Leukemia

Authors

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

Publication Date

6-1-2022

Journal

Haematologica

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.

Keywords

Animals, Apoptosis, Bridged Bicyclo Compounds, Heterocyclic, Cell Line, Tumor, Drug Resistance, Neoplasm, Extracellular Signal-Regulated MAP Kinases, Humans, Leukemia, Myeloid, Acute, Mice, Myeloid Cell Leukemia Sequence 1 Protein, Protein Kinase Inhibitors, Proteomics, Sulfonamides, c-Mer Tyrosine Kinase, fms-Like Tyrosine Kinase 3

DOI

10.3324/haematol.2021.278369

PMID

34732043

PMCID

PMC9152975

PubMedCentral® Posted Date

11-4-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes