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

AACR logo

  • 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
      • COVID-19 & Cancer Resource Center
      • Focus on Radiation Oncology
      • Novel Combinations
      • Reviews
      • 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
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

  • 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
  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Focus on Radiation Oncology
      • Novel Combinations
      • Reviews
      • 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
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

Preclinical Development

Targeting KRAS-Mutant Non–Small Cell Lung Cancer with the Hsp90 Inhibitor Ganetespib

Jaime Acquaviva, Donald L. Smith, Jim Sang, Julie C. Friedland, Suqin He, Manuel Sequeira, Chaohua Zhang, Yumiko Wada and David A. Proia
Jaime Acquaviva
Synta Pharmaceuticals Corp., Lexington, Massa-chusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Donald L. Smith
Synta Pharmaceuticals Corp., Lexington, Massa-chusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jim Sang
Synta Pharmaceuticals Corp., Lexington, Massa-chusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Julie C. Friedland
Synta Pharmaceuticals Corp., Lexington, Massa-chusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Suqin He
Synta Pharmaceuticals Corp., Lexington, Massa-chusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Manuel Sequeira
Synta Pharmaceuticals Corp., Lexington, Massa-chusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chaohua Zhang
Synta Pharmaceuticals Corp., Lexington, Massa-chusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yumiko Wada
Synta Pharmaceuticals Corp., Lexington, Massa-chusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David A. Proia
Synta Pharmaceuticals Corp., Lexington, Massa-chusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1158/1535-7163.MCT-12-0615
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Mutant KRAS is a feature of more than 25% of non–small cell lung cancers (NSCLC) and represents one of the most prevalent oncogenic drivers in this disease. NSCLC tumors with oncogenic KRAS respond poorly to current therapies, necessitating the pursuit of new treatment strategies. Targeted inhibition of the molecular chaperone Hsp90 results in the coordinated blockade of multiple oncogenic signaling pathways in tumor cells and has thus emerged as an attractive avenue for therapeutic intervention in human malignancies. Here, we examined the activity of ganetespib, a small-molecule inhibitor of Hsp90 currently in clinical trials for NSCLCs in a panel of lung cancer cell lines harboring a diverse spectrum of KRAS mutations. In vitro, ganetespib was potently cytotoxic in all lines, with concomitant destabilization of KRAS signaling effectors. Combinations of low-dose ganetespib with MEK or PI3K/mTOR inhibitors resulted in superior cytotoxic activity than single agents alone in a subset of mutant KRAS cells, and the antitumor efficacy of ganetespib was potentiated by cotreatment with the PI3K/mTOR inhibitor BEZ235 in A549 xenografts in vivo. At the molecular level, ganetespib suppressed activating feedback signaling loops that occurred in response to MEK and PI3K/mTOR inhibition, although this activity was not the sole determinant of combinatorial benefit. In addition, ganetespib sensitized mutant KRAS NSCLC cells to standard-of-care chemotherapeutics of the antimitotic, topoisomerase inhibitor, and alkylating agent classes. Taken together, these data underscore the promise of ganetespib as a single-agent or combination treatment in KRAS-driven lung tumors. Mol Cancer Ther; 11(12); 1–11. ©2012 AACR.

Footnotes

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

  • Received June 20, 2012.
  • Revision received August 17, 2012.
  • Accepted September 18, 2012.
  • ©2012 American Association for Cancer Research.
Next
Back to top

This OnlineFirst version was published on November 30, 2012
doi: 10.1158/1535-7163.MCT-12-0615

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.
Targeting KRAS-Mutant Non–Small Cell Lung Cancer with the Hsp90 Inhibitor Ganetespib
(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.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Targeting KRAS-Mutant Non–Small Cell Lung Cancer with the Hsp90 Inhibitor Ganetespib
Jaime Acquaviva, Donald L. Smith, Jim Sang, Julie C. Friedland, Suqin He, Manuel Sequeira, Chaohua Zhang, Yumiko Wada and David A. Proia
Mol Cancer Ther November 30 2012 DOI: 10.1158/1535-7163.MCT-12-0615

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Targeting KRAS-Mutant Non–Small Cell Lung Cancer with the Hsp90 Inhibitor Ganetespib
Jaime Acquaviva, Donald L. Smith, Jim Sang, Julie C. Friedland, Suqin He, Manuel Sequeira, Chaohua Zhang, Yumiko Wada and David A. Proia
Mol Cancer Ther November 30 2012 DOI: 10.1158/1535-7163.MCT-12-0615
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
  • Figures & Data
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • BMS-754807 Enhances Gemcitabine Response in PDAC
  • PSMA-Specific BiTE Antibody
  • BiKEs and TriKEs Enhance NK Cell Effector Function
Show more Preclinical Development
  • 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

About MCT

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

Copyright © 2021 by the American Association for Cancer Research.

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

Advertisement