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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
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