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

Resistance to Avapritinib in PDGFRA-Driven GIST Is Caused by Secondary Mutations in the PDGFRA Kinase Domain

Susanne Grunewald, Lillian R. Klug, Thomas Mühlenberg, Jonas Lategahn, Johanna Falkenhorst, Ajia Town, Christiane Ehrt, Eva Wardelmann, Wolfgang Hartmann, Hans-Ulrich Schildhaus, Juergen Treckmann, Jonathan A. Fletcher, Sascha Jung, Paul Czodrowski, Stephen Miller, Oleg Schmidt-Kittler, Daniel Rauh, Michael C. Heinrich and Sebastian Bauer
Susanne Grunewald
1Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany.
2DKTK partner site Essen, German Cancer Consortium (DKTK), Heidelberg, Germany.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lillian R. Klug
3Portland VA Health Care System, Portland, Oregon; Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon; and Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Thomas Mühlenberg
1Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany.
2DKTK partner site Essen, German Cancer Consortium (DKTK), Heidelberg, Germany.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Thomas Mühlenberg
Jonas Lategahn
4Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany.
5Drug Discovery Hub Dortmund (DDHD) am Zentrum für Integrierte Wirkstoffforschung (ZIW), Dortmund, Germany.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Jonas Lategahn
Johanna Falkenhorst
1Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany.
2DKTK partner site Essen, German Cancer Consortium (DKTK), Heidelberg, Germany.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Johanna Falkenhorst
Ajia Town
3Portland VA Health Care System, Portland, Oregon; Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon; and Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christiane Ehrt
4Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany.
5Drug Discovery Hub Dortmund (DDHD) am Zentrum für Integrierte Wirkstoffforschung (ZIW), Dortmund, Germany.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eva Wardelmann
6Gerhard-Domagk-Institute of Pathology, University of Münster Medical Center, Münster, Germany.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Eva Wardelmann
Wolfgang Hartmann
6Gerhard-Domagk-Institute of Pathology, University of Münster Medical Center, Münster, Germany.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hans-Ulrich Schildhaus
7Institute of Pathology, University Medical Center Essen, Essen, Germany.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Hans-Ulrich Schildhaus
Juergen Treckmann
8Department of Visceral Surgery, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jonathan A. Fletcher
9Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sascha Jung
4Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul Czodrowski
4Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Paul Czodrowski
Stephen Miller
10Blueprint Medicines, Cambridge, Massachusetts.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Oleg Schmidt-Kittler
10Blueprint Medicines, Cambridge, Massachusetts.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel Rauh
4Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany.
5Drug Discovery Hub Dortmund (DDHD) am Zentrum für Integrierte Wirkstoffforschung (ZIW), Dortmund, Germany.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Daniel Rauh
Michael C. Heinrich
3Portland VA Health Care System, Portland, Oregon; Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon; and Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Michael C. Heinrich
Sebastian Bauer
1Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany.
2DKTK partner site Essen, German Cancer Consortium (DKTK), Heidelberg, Germany.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Sebastian Bauer
  • For correspondence: sebastian.bauer@uk-essen.de
DOI: 10.1158/2159-8290.CD-20-0487 Published January 2021
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

This article requires a subscription to view the full text. You may purchase access to this article or login to access your subscription using the links below.

Abstract

Gastrointestinal stromal tumors (GIST) harboring activating mutations of PDGFRA respond to imatinib, with the notable exception of the most common mutation, D842V. Avapritinib is a novel, potent KIT/PDGFRA inhibitor with substantial clinical activity in patients with the D842V genotype. To date, only a minority of PDGFRA-mutant patients treated with avapritinib have developed secondary resistance. Tumor and plasma biopsies in 6 of 7 patients with PDGFRA primary mutations who progressed on avapritinib or imatinib had secondary resistance mutations within PDGFRA exons 13, 14, and 15 that interfere with avapritinib binding. Secondary PDGFRA mutations causing V658A, N659K, Y676C, and G680R substitutions were found in 2 or more patients each, representing recurrent mechanisms of PDGFRA GIST drug resistance. Notably, most PDGFRA-mutant GISTs refractory to avapritinib remain dependent on the PDGFRA oncogenic signal. Inhibitors that target PDGFRA protein stability or inhibition of PDGFRA-dependent signaling pathways may overcome avapritinib resistance.

Significance: Here, we provide the first description of avapritinib resistance mechanisms in PDGFRA-mutant GIST.

This article is highlighted in the In This Issue feature, p. 1

Footnotes

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

  • Cancer Discov 2021;11:108–25

  • Received May 14, 2020.
  • Revision received August 21, 2020.
  • Accepted September 21, 2020.
  • Published first September 24, 2020.
  • ©2020 American Association for Cancer Research.
View Full Text

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top
Cancer Discovery: 11 (1)
January 2021
Volume 11, Issue 1
  • 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.
Resistance to Avapritinib in PDGFRA-Driven GIST Is Caused by Secondary Mutations in the PDGFRA Kinase Domain
(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
Resistance to Avapritinib in PDGFRA-Driven GIST Is Caused by Secondary Mutations in the PDGFRA Kinase Domain
Susanne Grunewald, Lillian R. Klug, Thomas Mühlenberg, Jonas Lategahn, Johanna Falkenhorst, Ajia Town, Christiane Ehrt, Eva Wardelmann, Wolfgang Hartmann, Hans-Ulrich Schildhaus, Juergen Treckmann, Jonathan A. Fletcher, Sascha Jung, Paul Czodrowski, Stephen Miller, Oleg Schmidt-Kittler, Daniel Rauh, Michael C. Heinrich and Sebastian Bauer
Cancer Discov January 1 2021 (11) (1) 108-125; DOI: 10.1158/2159-8290.CD-20-0487

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Resistance to Avapritinib in PDGFRA-Driven GIST Is Caused by Secondary Mutations in the PDGFRA Kinase Domain
Susanne Grunewald, Lillian R. Klug, Thomas Mühlenberg, Jonas Lategahn, Johanna Falkenhorst, Ajia Town, Christiane Ehrt, Eva Wardelmann, Wolfgang Hartmann, Hans-Ulrich Schildhaus, Juergen Treckmann, Jonathan A. Fletcher, Sascha Jung, Paul Czodrowski, Stephen Miller, Oleg Schmidt-Kittler, Daniel Rauh, Michael C. Heinrich and Sebastian Bauer
Cancer Discov January 1 2021 (11) (1) 108-125; DOI: 10.1158/2159-8290.CD-20-0487
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
    • Authors' Disclosures
    • Authors' Contributions
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • Personalized Antibodies for Gastroesophageal Adenocarcinoma
  • Fibroblastic NetG1 Promotes Pancreatic Cancer
  • Angiopoietin-2 in Lymphatic Metastasis
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