Targeting CCNE1 amplified ovarian and endometrial cancers by combined inhibition of PKMYT1 and ATR.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 40169546.
- Also identified by DOI 10.1038/s41467-025-58183-w and PMC identifier 11962063.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Cyclin E
- Endometrial Neoplasms
- Ovarian Neoplasms
- Ataxia Telangiectasia Mutated Proteins
- Oncogene Proteins