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
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Collections
      • COVID-19 & Cancer Resource Center
      • Precision Medicine and Therapeutic Resistance
      • 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
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Collections
      • COVID-19 & Cancer Resource Center
      • Precision Medicine and Therapeutic Resistance
      • 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 Watch

Newly Synthesized KRASG12C Mediates Escape from KRASG12C Inhibition

DOI: 10.1158/2159-8290.CD-RW2020-010 Published March 2020
  • Article
  • Info & Metrics
  • PDF
Loading
  • Major Finding: KRASG12C-mutant cells treated with KRASG12C inhibitors quickly became either quiescent or resistant.

  • Mechanism: Cells that escape inhibition have large pools of newly synthesized, rapidly activated KRASG12C.

  • Impact: Further study of this mechanism is necessary if KRASG12C inhibitors are to elicit durable responses.

Inhibitors of the oncoprotein KRASG12C are currently in phase I clinical trials, with preliminary data suggesting that the drugs are effective in some patients with lung adenocarcinoma. Possible resistance mechanisms to KRASG12C inhibitors, which selectively bind and trap the mutant protein in its inactive state, are not yet known. To investigate this, Xue, Zhao, and colleagues performed single-cell RNA-sequencing analyses on cells from three lung cancer lines harboring the KRASG12C mutation treated with the covalent KRASG12C inhibitor ARS1620 for zero, four, 24, or 72 hours. These experiments revealed that, shortly after treatment initiation, most cells were sequestered in a quiescent state with low expression of KRASG12C-dependent genes; however, some cells appeared to be able to circumvent the effects of KRASG12C inhibition after a relatively short treatment duration. Further experiments implicated EGFR signaling and AURKA as being crucial to KRASG12C-mutant cells' ability escape from ARS1620-induced quiescence. Mechanistically, the ability of some cells to bypass KRASG12C inhibition seemed to be due to the fact that a pool of newly synthesized KRASG12C is able to maintain activity by undergoing nucleotide exchange prior to drug binding. Treatment with ARS1620 thus eliminates cells that lack adequate KRASG12C expression and selects for cells with a large pool of new KRASG12C that can be rapidly activated as a result of upstream signals. In summary, this work elucidates a previously unknown mechanism of resistance to KRASG12C inhibitors and suggests that further study into ways to quash this mechanism are necessary to ensure that responses to this new class of drugs are durable.

Xue JY, Zhao Y, Aronowitz J, Mai TT, Vides A, Qeriqi B, et al. Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition. Nature 2020;577:421–5.

Notes

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.

  • ©2020 American Association for Cancer Research.
PreviousNext
Back to top
Cancer Discovery: 10 (3)
March 2020
Volume 10, Issue 3
  • 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.
Newly Synthesized KRASG12C Mediates Escape from KRASG12C Inhibition
(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
Newly Synthesized KRASG12C Mediates Escape from KRASG12C Inhibition
Cancer Discov March 1 2020 (10) (3) 341; DOI: 10.1158/2159-8290.CD-RW2020-010

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Newly Synthesized KRASG12C Mediates Escape from KRASG12C Inhibition
Cancer Discov March 1 2020 (10) (3) 341; DOI: 10.1158/2159-8290.CD-RW2020-010
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
    • Notes
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

Research Watch

  • Cell-Intrinsic Programs Partition Nutrients in Tumor Microenvironment
  • Extrachromosomal DNA Can Promote Oncogene Transcription in Trans
  • Transient Rest Reverses Exhaustion of Chimeric Antigen Receptor T Cells
Show more Research Watch

Drug Resistance

  • Resistance-Linked Stress-Induced Mutagenesis Is MTOR-Mediated in Cancer
  • YAP Mediates EGFR Inhibitor–Induced Dormancy in EGFR-Mutant Cancer
Show more Drug Resistance
  • 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