Dual Targeting of Aurora Kinases with AMG 900 Exhibits Potent Preclinical Activity Against Acute Myeloid Leukemia with Distinct Post-Mitotic Outcomes

• Published in: Molecular cancer therapeutics 2018-12, Vol.17 (12), p.2575-2585
• Main Authors: Payton, Marc, Cheung, Hung-Kam, Ninniri, Maria Stefania S, Marinaccio, Christian, Wayne, William C, Hanestad, Kelly, Crispino, John D, Juan, Gloria, Coxon, Angela
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Aurora Kinases - antagonists & inhibitors; Aurora Kinases - metabolism; Cell Cycle Checkpoints - drug effects; Cell Differentiation - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Female; G1 Phase - drug effects; Humans; Leukemia, Myeloid, Acute - pathology; Megakaryocytes - drug effects; Megakaryocytes - metabolism; Megakaryocytes - pathology; Mice; Mitosis - drug effects; Organophosphates - pharmacology; Phthalazines - pharmacology; Polyploidy; Protein Isoforms - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Quinazolines - pharmacology; Tumor Burden; Tumor Suppressor Protein p53 - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-18-0186

Aurora kinase A and B have essential and non-overlapping roles in mitosis, with elevated expression in a subset of human cancers, including acute myeloid leukemia (AML). In this study, pan-aurora kinase inhibitor (AKI) AMG 900 distinguishes itself as an anti-leukemic agent that is more uniformly potent against a panel of AML cell lines than are isoform-selective AKIs and classic AML drugs. AMG 900 inhibited AML cell growth by inducing polyploidization and/or apoptosis. AMG 900 and aurora-B-selective inhibitor AZD1152-hQPA showed comparable cellular effects on AML lines that do not harbor a -ITD mutation. AMG 900 was active against P-glycoprotein-expressing AML cells resistant to AZD1152-hQPA and was effective at inducing expression of megakaryocyte-lineage markers (CD41, CD42) on human CHRF-288-11 cells and mouse cells. In MOLM-13 cells, inhibition of p-histone H3 by AMG 900 was associated with polyploidy, extra centrosomes, accumulation of p53 protein, apoptosis, and cleavage of Bcl-2 protein. Co-administration of cytarabine (Ara-C) with AMG 900 potentiated cell killing in a subset of AML lines, with evidence of attenuated polyploidization. AMG 900 inhibited the proliferation of primary human bone marrow cells in culture, with a better proliferation recovery profile relative to classic antimitotic drug docetaxel. , AMG 900 significantly reduced tumor burden in a systemic MOLM-13 xenograft model where we demonstrate the utility of 3'-deoxy-3'- F-fluorothymidine [ F]FLT positron emission tomographic (PET)-CT imaging to measure the antiproliferative effects of AMG 900 in skeletal tissues in mice.