Skip to main content
  • AACR Journals
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Collections
      • Focus on Radiation Oncology
      • Novel Combinations
      • Reviews
      • Editors' Picks
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • OnlineFirst
    • Editors' Picks
    • Citation
    • Author/Keyword
  • News
    • Cancer Discovery News
  • AACR Journals
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in
  • My Cart

Search

  • Advanced search
Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

Advanced Search

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Collections
      • Focus on Radiation Oncology
      • Novel Combinations
      • Reviews
      • Editors' Picks
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • OnlineFirst
    • Editors' Picks
    • Citation
    • Author/Keyword
  • News
    • Cancer Discovery News
Small Molecule Therapeutics

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

Marc Payton, Hung-Kam Cheung, Maria Stefania S. Ninniri, Christian Marinaccio, William C. Wayne, Kelly Hanestad, John D. Crispino, Gloria Juan and Angela Coxon
Marc Payton
Amgen Discovery Research, Thousand Oaks, California.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: mpayton@amgen.com
Hung-Kam Cheung
Amgen Medical Sciences, Thousand Oaks, California.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Maria Stefania S. Ninniri
Amgen Discovery Research, Thousand Oaks, California.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christian Marinaccio
Division of Hematology/Oncology, Northwestern University, Chicago, Illinois.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
William C. Wayne
Amgen Discovery Research, Thousand Oaks, California.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kelly Hanestad
Amgen Discovery Research, Thousand Oaks, California.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John D. Crispino
Division of Hematology/Oncology, Northwestern University, Chicago, Illinois.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gloria Juan
Amgen Medical Sciences, Thousand Oaks, California.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Angela Coxon
Amgen Discovery Research, Thousand Oaks, California.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1158/1535-7163.MCT-18-0186 Published December 2018
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

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 FLT3-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 Jak2V617F 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. In vivo, AMG 900 significantly reduced tumor burden in a systemic MOLM-13 xenograft model where we demonstrate the utility of 3′-deoxy-3′-18F-fluorothymidine [18F]FLT positron emission tomographic (PET)–CT imaging to measure the antiproliferative effects of AMG 900 in skeletal tissues in mice.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received February 22, 2018.
  • Revision received June 15, 2018.
  • Accepted September 25, 2018.
  • Published first September 28, 2018.
  • ©2018 American Association for Cancer Research.
View Full Text
PreviousNext
Back to top
Molecular Cancer Therapeutics: 17 (12)
December 2018
Volume 17, Issue 12
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Editorial Board (PDF)

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Cancer Therapeutics article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Dual Targeting of Aurora Kinases with AMG 900 Exhibits Potent Preclinical Activity Against Acute Myeloid Leukemia with Distinct Post-Mitotic Outcomes
(Your Name) has forwarded a page to you from Molecular Cancer Therapeutics
(Your Name) thought you would be interested in this article in Molecular Cancer Therapeutics.
Citation Tools
Dual Targeting of Aurora Kinases with AMG 900 Exhibits Potent Preclinical Activity Against Acute Myeloid Leukemia with Distinct Post-Mitotic Outcomes
Marc Payton, Hung-Kam Cheung, Maria Stefania S. Ninniri, Christian Marinaccio, William C. Wayne, Kelly Hanestad, John D. Crispino, Gloria Juan and Angela Coxon
Mol Cancer Ther December 1 2018 (17) (12) 2575-2585; DOI: 10.1158/1535-7163.MCT-18-0186

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Dual Targeting of Aurora Kinases with AMG 900 Exhibits Potent Preclinical Activity Against Acute Myeloid Leukemia with Distinct Post-Mitotic Outcomes
Marc Payton, Hung-Kam Cheung, Maria Stefania S. Ninniri, Christian Marinaccio, William C. Wayne, Kelly Hanestad, John D. Crispino, Gloria Juan and Angela Coxon
Mol Cancer Ther December 1 2018 (17) (12) 2575-2585; DOI: 10.1158/1535-7163.MCT-18-0186
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Disclosure of Potential Conflicts of Interest
    • Authors' Contributions
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • Morin Induces CML Apoptosis by the miR-188-5p/PTEN/AKT Axis
  • FGF401 Selectively Targets FGF19+ Hepatocellular Tumors
  • CDK4/6 Inhibition in Early-Stage Breast Cancer
Show more Small Molecule Therapeutics
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook  Twitter  LinkedIn  YouTube  RSS

Articles

  • Online First
  • Current Issue
  • Past Issues
  • Meeting Abstracts

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians
  • Reviewers

About MCT

  • About the Journal
  • Editorial Board
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2019 by the American Association for Cancer Research.

Molecular Cancer Therapeutics
eISSN: 1538-8514
ISSN: 1535-7163

Advertisement