Targeting CCNE1 amplified ovarian and endometrial cancers by combined inhibition of PKMYT1 and ATR
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 hyp...
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| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58183-w |
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| Summary: | 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. |
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| ISSN: | 2041-1723 |