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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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    1. Arindam Datta & Kajal Biswas & Joshua A. Sommers & Haley Thompson & Sanket Awate & Claudia M. Nicolae & Tanay Thakar & George-Lucian Moldovan & Robert H. Shoemaker & Shyam K. Sharan & Robert M. Brosh, 2021. "WRN helicase safeguards deprotected replication forks in BRCA2-mutated cancer cells," Nature Communications, Nature, vol. 12(1), pages 1-22, December.
    2. Hyoung Kim & Haineng Xu & Erin George & Dorothy Hallberg & Sushil Kumar & Veena Jagannathan & Sergey Medvedev & Yasuto Kinose & Kyle Devins & Priyanka Verma & Kevin Ly & Yifan Wang & Roger A. Greenber, 2020. "Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    3. Ann-Marie Patch & Elizabeth L. Christie & Dariush Etemadmoghadam & Dale W. Garsed & Joshy George & Sian Fereday & Katia Nones & Prue Cowin & Kathryn Alsop & Peter J. Bailey & Karin S. Kassahn & Felici, 2015. "Whole–genome characterization of chemoresistant ovarian cancer," Nature, Nature, vol. 521(7553), pages 489-494, May.
    4. Sylvie M. Noordermeer & Salomé Adam & Dheva Setiaputra & Marco Barazas & Stephen J. Pettitt & Alexanda K. Ling & Michele Olivieri & Alejandro Álvarez-Quilón & Nathalie Moatti & Michal Zimmermann & Ste, 2018. "The shieldin complex mediates 53BP1-dependent DNA repair," Nature, Nature, vol. 560(7716), pages 117-121, August.
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