The new small tyrosine kinase inhibitor ARQ531 targets acute myeloid leukemia cells by disrupting multiple tumor-addicted programs.

Abstract

Tyrosine kinases have been implicated in promoting tumorigenesis of several human cancers. Exploiting these vulnerabilities has been shown to be an effective anti-tumor strategy as demonstrated for example by the Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, for treatment of various blood cancers. Here, we characterize a new multiple kinase inhibitor, ARQ531, and evaluate its mechanism of action in preclinical models of acute myeloid leukemia. Treatment with ARQ531, by producing global signaling pathway deregulation, resulted in impaired cell cycle progression and survival in a large panel of leukemia cell lines and patient-derived tumor cells, regardless of the specific genetic background and/or the presence of bone marrow stromal cells. RNA-seq analysis revealed that ARQ531 constrained tumor cell proliferation and survival through Bruton's tyrosine kinase and transcriptional program dysregulation, with proteasome-mediated MYB degradation and depletion of short-lived proteins that are crucial for tumor growth and survival, including ERK, MYC and MCL1. Finally, ARQ531 treatment was effective in a patient-derived leukemia mouse model with significant impairment of tumor progression and survival, at tolerated doses. These data justify the clinical development of ARQ531 as a promising targeted agent for the treatment of patients with acute myeloid leukemia.

• Authors: Debora Soncini, Stefania Orecchioni, Samantha Ruberti, Paola Minetto, Claudia Martinuzzi, Luca Agnelli, Katia Todoerti, Antonia Cagnetta, Maurizio Miglino, Marino Clavio, Paola Contini, Riccardo Varaldo, Micaela Bergamaschi, Fabio Guolo, Mario Passalacqua, Alessio Nencioni, Fiammetta Monacelli, Marco Gobbi, Antonino Neri, Giovanni Abbadessa, Sudharshan Eathiraj, Brian Schwartz, Francesco Bertolini, Roberto M Lemoli, Michele Cea
• Journal: Haematologica (Haematologica) Vol. 105 Issue 10 Pg. 2420-2431 (10 01 2020) ISSN: 1592-8721 [Electronic] Italy
• PMID: 33054082 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• Pyrimidines
• Protein-Tyrosine Kinases
• Agammaglobulinaemia Tyrosine Kinase

Topics

• Agammaglobulinaemia Tyrosine Kinase
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Protein-Tyrosine Kinases
• Pyrimidines