Skip to main content
  • AACR Publications
    • 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

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Journal Sections
    • Subscriptions
    • Reviewing
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Collections
      • COVID-19 & Cancer Resource Center
      • Clinical Trials
      • Immuno-oncology
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
    • Journal Press Releases
  • COVID-19
  • Webinars
  • 10th Anniversary
  • Search More

    Advanced Search

  • AACR Publications
    • 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
Cancer Discovery
Cancer Discovery
  • Home
  • About
    • The Journal
    • AACR Journals
    • Journal Sections
    • Subscriptions
    • Reviewing
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Collections
      • COVID-19 & Cancer Resource Center
      • Clinical Trials
      • Immuno-oncology
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
    • Journal Press Releases
  • COVID-19
  • Webinars
  • 10th Anniversary
  • Search More

    Advanced Search

Research Articles

A Novel MCL1 Inhibitor Combined with Venetoclax Rescues Venetoclax-Resistant Acute Myelogenous Leukemia

Haley E. Ramsey, Melissa A. Fischer, Taekyu Lee, Agnieszka E. Gorska, Maria Pia Arrate, Londa Fuller, Kelli L. Boyd, Stephen A. Strickland, John Sensintaffar, Leah J. Hogdal, Gregory D. Ayers, Edward T. Olejniczak, Stephen W. Fesik and Michael R. Savona
Haley E. Ramsey
1Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Melissa A. Fischer
1Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Melissa A. Fischer
Taekyu Lee
2Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee.
3Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, Tennessee.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Agnieszka E. Gorska
1Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Maria Pia Arrate
1Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Londa Fuller
1Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kelli L. Boyd
4Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephen A. Strickland
1Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
5Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John Sensintaffar
2Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Leah J. Hogdal
2Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gregory D. Ayers
5Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
6Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee.
7Vanderbilt Center for Quantitative Sciences, Vanderbilt University, Nashville, Tennessee.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Edward T. Olejniczak
2Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee.
3Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, Tennessee.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephen W. Fesik
2Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee.
3Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, Tennessee.
5Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael R. Savona
1Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
5Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Michael R. Savona
  • For correspondence: michael.savona@vanderbilt.edu
DOI: 10.1158/2159-8290.CD-18-0140 Published December 2018
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Suppression of apoptosis by expression of antiapoptotic BCL2 family members is a hallmark of acute myeloblastic leukemia (AML). Induced myeloid leukemia cell differentiation protein (MCL1), an antiapoptotic BCL2 family member, is commonly upregulated in AML cells and is often a primary mode of resistance to treatment with the BCL2 inhibitor venetoclax. Here, we describe VU661013, a novel, potent, selective MCL1 inhibitor that destabilizes BIM/MCL1 association, leads to apoptosis in AML, and is active in venetoclax-resistant cells and patient-derived xenografts. In addition, VU661013 was safely combined with venetoclax for synergy in murine models of AML. Importantly, BH3 profiling of patient samples and drug-sensitivity testing ex vivo accurately predicted cellular responses to selective inhibitors of MCL1 or BCL2 and showed benefit of the combination. Taken together, these data suggest a strategy of rationally using BCL2 and MCL1 inhibitors in sequence or in combination in AML clinical trials.

Significance: Targeting antiapoptotic proteins in AML is a key therapeutic strategy, and MCL1 is a critical antiapoptotic oncoprotein. Armed with novel MCL1 inhibitors and the potent BCL2 inhibitor venetoclax, it may be possible to selectively induce apoptosis by combining or thoughtfully sequencing these inhibitors based on a rational evaluation of AML.

See related commentary by Leber et al., p. 1511.

This article is highlighted in the In This Issue feature, p. 1494

Footnotes

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

  • Received February 14, 2018.
  • Revision received July 14, 2018.
  • Accepted August 28, 2018.
  • Published first September 5, 2018.
  • ©2018 American Association for Cancer Research.
View Full Text
PreviousNext
Back to top
Cancer Discovery: 8 (12)
December 2018
Volume 8, 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 Cancer Discovery 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.
A Novel MCL1 Inhibitor Combined with Venetoclax Rescues Venetoclax-Resistant Acute Myelogenous Leukemia
(Your Name) has forwarded a page to you from Cancer Discovery
(Your Name) thought you would be interested in this article in Cancer Discovery.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
A Novel MCL1 Inhibitor Combined with Venetoclax Rescues Venetoclax-Resistant Acute Myelogenous Leukemia
Haley E. Ramsey, Melissa A. Fischer, Taekyu Lee, Agnieszka E. Gorska, Maria Pia Arrate, Londa Fuller, Kelli L. Boyd, Stephen A. Strickland, John Sensintaffar, Leah J. Hogdal, Gregory D. Ayers, Edward T. Olejniczak, Stephen W. Fesik and Michael R. Savona
Cancer Discov December 1 2018 (8) (12) 1566-1581; DOI: 10.1158/2159-8290.CD-18-0140

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
A Novel MCL1 Inhibitor Combined with Venetoclax Rescues Venetoclax-Resistant Acute Myelogenous Leukemia
Haley E. Ramsey, Melissa A. Fischer, Taekyu Lee, Agnieszka E. Gorska, Maria Pia Arrate, Londa Fuller, Kelli L. Boyd, Stephen A. Strickland, John Sensintaffar, Leah J. Hogdal, Gregory D. Ayers, Edward T. Olejniczak, Stephen W. Fesik and Michael R. Savona
Cancer Discov December 1 2018 (8) (12) 1566-1581; DOI: 10.1158/2159-8290.CD-18-0140
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
    • Results
    • Discussion
    • Methods
    • 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

  • SREBP-Transferrin Regulatory Network in Melanoma CTCs
  • Machine-Learning Approach Predicts Hippo Pathway Dependency
  • Type II RAFi and MEKi to Treat MAPK-Addicted Cancers
Show more Research Articles
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook   Twitter   LinkedIn   YouTube   RSS

Articles

  • OnlineFirst
  • Current Issue
  • Past Issues

Info For

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About Cancer Discovery

  • About the Journal
  • Editors
  • Journal Sections
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2021 by the American Association for Cancer Research.

Cancer Discovery
eISSN: 2159-8290
ISSN: 2159-8274

Advertisement