IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-58183-w.html
   My bibliography  Save this article

Targeting CCNE1 amplified ovarian and endometrial cancers by combined inhibition of PKMYT1 and ATR

Author

Listed:
  • Haineng Xu

    (University of Pennsylvania
    Hospital of the University of Pennsylvania)

  • Erin George

    (University of Pennsylvania
    Hospital of the University of Pennsylvania
    H. Lee Moffitt Cancer Center and Research Institute)

  • David Gallo

    (7171 Frederick-Banting
    University of Wisconsin-Madison)

  • Sergey Medvedev

    (University of Pennsylvania
    Hospital of the University of Pennsylvania)

  • Xiaolei Wang

    (University of Pennsylvania
    Hospital of the University of Pennsylvania)

  • Arindam Datta

    (University of Pennsylvania)

  • Rosie Kryczka

    (7171 Frederick-Banting)

  • Marc L. Hyer

    (101 Main St)

  • Jimmy Fourtounis

    (7171 Frederick-Banting)

  • Rino Stocco

    (7171 Frederick-Banting)

  • Elia Aguado-Fraile

    (101 Main St)

  • Adam Petrone

    (101 Main St)

  • Shou Yun Yin

    (7171 Frederick-Banting)

  • Ariya Shiwram

    (7171 Frederick-Banting)

  • Fang Liu

    (University of Pennsylvania
    Hospital of the University of Pennsylvania)

  • Matthew Anderson

    (University of Pennsylvania
    Hospital of the University of Pennsylvania)

  • Hyoung Kim

    (University of Pennsylvania
    Hospital of the University of Pennsylvania)

  • Roger A. Greenberg

    (University of Pennsylvania)

  • C. Gary Marshall

    (101 Main St)

  • Fiona Simpkins

    (University of Pennsylvania
    Hospital of the University of Pennsylvania)

Abstract

Ovarian cancers (OVCAs) and endometrial cancers (EMCAs) with CCNE1-amplification are often resistant to standard treatment and represent an unmet clinical need. Synthetic-lethal screening identified loss of the CDK1 regulator, PKMYT1, as synthetically lethal with CCNE1-amplification. We hypothesize that CCNE1-amplification associated replication stress will be more effectively targeted by combining PKMYT1 inhibitor lunresertib (RP-6306), with ATR inhibitor camonsertib (RP-3500/RG6526). Low dose combination RP-6306 with RP-3500 synergistically increases cytotoxicity more so in CCNE1-amplified compared to non-amplified cells. Combination treatment produces durable antitumor activity, reduces metastasis and increases survival in CCNE1-amplified patient-derived OVCA and EMCA xenografts. Mechanistically, low doses of RP-6306 with RP-3500 increase CDK1 activation more so than monotherapy, triggering rapid and robust induction of premature mitosis, DNA damage, and apoptosis in a CCNE1-dependent manner. These findings suggest that targeting CDK1 activity by combining RP-6306 with RP-3500 is an effective therapeutic approach to treat CCNE1-amplifed OVCAs and EMCAs.

Suggested Citation

  • Haineng Xu & Erin George & David Gallo & Sergey Medvedev & Xiaolei Wang & Arindam Datta & Rosie Kryczka & Marc L. Hyer & Jimmy Fourtounis & Rino Stocco & Elia Aguado-Fraile & Adam Petrone & Shou Yun Y, 2025. "Targeting CCNE1 amplified ovarian and endometrial cancers by combined inhibition of PKMYT1 and ATR," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58183-w
    DOI: 10.1038/s41467-025-58183-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-58183-w
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-58183-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58183-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.