Targeting CCNE1 amplified ovarian and endometrial cancers by combined inhibition of PKMYT1 and ATR

作者：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 Yin, Ariya Shiwram, Fang Liu, Matthew Anderson, Hyoung Kim, Roger A. Greenberg, Cooper Marshall, Fiona Simpkins · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-58183-w · 被引用次数：23 · 研究领域：PARP inhibition in cancer therapy、DNA Repair Mechanisms、Cancer-related Molecular Pathways

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.