Targeting CCNE1 amplified ovarian and endometrial cancers by combined inhibition of PKMYT1 and ATR
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.
Authors
- Haineng Xu (ORCID: https://orcid.org/0000-0001-7195-4897)
- Rosie Kryczka
- Elia Aguado-Fraile
- Fiona Simpkins (ORCID: https://orcid.org/0000-0002-0840-2368)
- Shou Yun Yin
- Arindam Datta (ORCID: https://orcid.org/0000-0002-0617-9908)
- Erin George (ORCID: https://orcid.org/0000-0003-3068-0273)
- Adam Petrone
- Hyoung Kim (ORCID: https://orcid.org/0000-0002-9975-8545)
- Roger A. Greenberg (ORCID: https://orcid.org/0000-0003-1326-8981)
- Jimmy Fourtounis
- Marc L. Hyer (ORCID: https://orcid.org/0009-0003-3737-1542)
- Cooper Marshall
- Ariya Shiwram
- Xiaolei Wang (ORCID: https://orcid.org/0000-0001-5441-0855)
- Fang Liu (ORCID: https://orcid.org/0000-0003-2922-4414)
- Matthew Anderson (ORCID: https://orcid.org/0009-0006-5555-5822)
- Rino Stocco
- Sergey Medvedev
- David Gallo
Institutions
- University of Wisconsin–Madison (US)
- Hospital of the University of Pennsylvania (US)
- Moffitt Cancer Center (US)
- Cancer Research Center (US)
- Penn Center for AIDS Research (US)
- Io Therapeutics (United States) (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1038/s41467-025-58183-w
- Citations
- 17
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 16.73
Funders
- Foundation for Women's Cancer
- University of Pennsylvania
- National Institutes of Health
- National Cancer Institute