Skip to main content
  • AACR Publications
    • 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
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Focus on Computer Resources
    • 75th Anniversary
    • Meeting Abstracts
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • OnlineFirst
    • Editors' Picks
    • Citations
    • Author/Keyword
  • News
    • Cancer Discovery News
  • AACR Publications
    • 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

Search

  • Advanced search
Cancer Research
Cancer Research

Advanced Search

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Focus on Computer Resources
    • 75th Anniversary
    • Meeting Abstracts
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • OnlineFirst
    • Editors' Picks
    • Citations
    • Author/Keyword
  • News
    • Cancer Discovery News
Tumor Biology

Abstract 1459: Combined inhibition of Wee1 and PARP1 sensitizes pancreatic cancer cells to radiation

David Karnak, Leslie A. Parsels, Jonathan Maybaum, Theodore S. Lawrence and Meredith Ann Morgan
David Karnak
1Univ. of Michigan, Ann Arbor, MI
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Leslie A. Parsels
1Univ. of Michigan, Ann Arbor, MI
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jonathan Maybaum
1Univ. of Michigan, Ann Arbor, MI
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Theodore S. Lawrence
1Univ. of Michigan, Ann Arbor, MI
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Meredith Ann Morgan
1Univ. of Michigan, Ann Arbor, MI
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1158/1538-7445.AM2012-1459 Published April 2012
  • Article
  • Info & Metrics
Loading
Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL

Abstract

PARP1 [poly (ADP-ribose) polymerase-1] inhibitors are maximally effective in cells with HRR (homologous recombination repair) defects, a concept known as synthetic lethality. We have previously shown that inhibition of HRR and the G2 checkpoint by small molecule inhibitors of Chk1 (checkpoint kinase 1), can induce synthetic lethality by increasing PARP1 inhibitor-mediated radiosensitization selectively in tumor cells and preferentially in tumor cells with p53 mutations. In order to begin to determine whether other inhibitors of the DNA damage response might induce synthetic lethality in combination with PARP1 inhibition and radiation, we evaluated MK-1775, a Wee1 kinase inhibitor. Wee1 regulates the G2 checkpoint by phosphorylation of Cdk1, thus preventing entry into mitosis in the presence of DNA damage, while its influence on HRR is not clear. To determine whether inhibition of Wee1 might synergistically radiosensitize in combination with PARP1 inhibition, we treated pancreatic cancer cells with MK-1775 (100-200nM) and the PARP1 inhibitor, olaparib (1uM) and assessed radiosensitization by clonogenic survival. We found that the combination of MK-1775 with olaparib induced marked radiosensitization in MiaPaCa-2 (RER: 1.9) and AsPC-1 (RER: 1.7) pancreatic cancer cells, which was greater than the radiosensitization produced by either agent alone. In order to determine the mechanism(s) by which Wee1 and PARP1 inhibitors interact to produce radiosensitization, we investigated the G2 checkpoint as well as HRR. In response to radiation, MK-1775 abrogated the G2 checkpoint while olaparib treatment resulted in increased G2 accumulation which was associated with increased γH2AX, suggesting the presence of unrepaired DNA double strand breaks. Abrogation of the olaparib+radiation-mediated G2 checkpoint, by MK-1775 resulted in even greater DNA damage as assessed by γH2AX expression. Given the efficacy of PARP1 inhibitors in HRR defective cells, we also investigated the effect of MK-1775 on HRR. We found that MK-1775 inhibited homology-directed repair of an I-SceI endonuclease-induced DNA double strand break in MiaPaCa-2 cells (Control 5.2% versus MK-1775 3.3%, P<0.05) as well as impaired Rad51 focus formation in response to radiation. Taken together, these results suggest that inhibition of HRR and the G2 checkpoint by inhibition of Wee1 can induce synthetic lethality with PARP1 inhibitors in combination with radiation by increasing unrepaired DNA double strand breaks. These studies support the continued investigation of combined molecularly targeted agents such as Wee1 and PARP1 inhibitors with radiation, to induce synthetic lethality selectively in tumor cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1459. doi:1538-7445.AM2012-1459

  • ©2012 American Association for Cancer Research
Back to top
Cancer Research: 72 (8 Supplement)
April 2012
Volume 72, Issue 8 Supplement
  • Table of Contents
  • Index by Author

Sign up for alerts

Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Cancer Research 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.
Abstract 1459: Combined inhibition of Wee1 and PARP1 sensitizes pancreatic cancer cells to radiation
(Your Name) has forwarded a page to you from Cancer Research
(Your Name) thought you would be interested in this article in Cancer Research.
Citation Tools
Abstract 1459: Combined inhibition of Wee1 and PARP1 sensitizes pancreatic cancer cells to radiation
David Karnak, Leslie A. Parsels, Jonathan Maybaum, Theodore S. Lawrence and Meredith Ann Morgan
Cancer Res April 15 2012 (72) (8 Supplement) 1459; DOI: 10.1158/1538-7445.AM2012-1459

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Abstract 1459: Combined inhibition of Wee1 and PARP1 sensitizes pancreatic cancer cells to radiation
David Karnak, Leslie A. Parsels, Jonathan Maybaum, Theodore S. Lawrence and Meredith Ann Morgan
Cancer Res April 15 2012 (72) (8 Supplement) 1459; DOI: 10.1158/1538-7445.AM2012-1459
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
  • Info & Metrics
Advertisement

Related Articles

Cited By...

More in this TOC Section

Tumor Biology

  • Abstract SY34-04: Do we need to know what pO2 hypoxia is
  • Abstract SY28-04: Rational incorporation of novel agents into multimodality treatment of glioma and neuroblastoma
  • Abstract SY28-02: Connections in the BRCA1-BRCA2 pathway of homologous recombination: Implications for breast cancer development and treatment
Show more 3

Poster Presentations - Proffered Abstracts

  • Abstract LB-236: Risk of tMDS/AML after chemotherapy for first primary lymphoid malignancy, 2000-2013
  • Abstract LB-001: Impact of direct physician engagement with racial/ethnic minorities for oncology clinical trial access and accrual model
  • Abstract LB-107: EV-TRACK: transparent reporting and centralizing knowledge of extracellular vesicles to support the validation of extracellular vesicle biomarkers in cancer research
Show more 3

Poster Presentations - Radiosensitizers and Radioprotectors

  • Abstract 1457: Valproic acid enhances radiation therapy by protecting normal hippocampal neurons and sensitizing malignant glioblastoma cells
  • Abstract 1467: Inhibition of Cdk4 radiosensitizes breast cancer cells by increasing PP2A levels, and decreasing Bad136 phosphorylation.
  • Abstract 1469: Radiosensitization of hepatocellular carcinoma using rationally combined molecular-targeted agents
Show more 3
  • Home
  • Alerts
  • Feedback
Facebook  Twitter  LinkedIn  YouTube  RSS

Articles

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

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians
  • Reviewers

About Cancer Research

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

Copyright © 2018 by the American Association for Cancer Research.

Cancer Research Online ISSN: 1538-7445
Cancer Research Print ISSN: 0008-5472
Journal of Cancer Research ISSN: 0099-7013
American Journal of Cancer ISSN: 0099-7374

Advertisement