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

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Nature Communications Pub Date : 2025-04-01 DOI:10.1038/s41467-025-58183-w

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, C. Gary Marshall, Fiona Simpkins

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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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通过联合抑制PKMYT1和ATR靶向CCNE1扩增卵巢癌和子宫内膜癌

ccne1扩增的卵巢癌（OVCAs）和子宫内膜癌（EMCAs）通常对标准治疗有耐药性，这代表了未满足的临床需求。合成致死性筛选发现CDK1调节因子PKMYT1的缺失与ccne1扩增具有合成致死性。我们假设，通过结合PKMYT1抑制剂lunresertib （RP-6306）和ATR抑制剂camonsertib (RP-3500/RG6526)， ccne1扩增相关的复制应激将更有效地靶向。低剂量RP-6306与RP-3500联合使用，在ccne1扩增细胞中，与非扩增细胞相比，其增效作用更大。在ccne1扩增的患者来源的OVCA和EMCA异种移植物中，联合治疗可产生持久的抗肿瘤活性，减少转移并提高生存率。从机制上讲，低剂量RP-6306联合RP-3500比单药治疗更能增加CDK1的激活，以依赖ccne1的方式快速而有力地诱导过早有丝分裂、DNA损伤和细胞凋亡。这些发现表明，结合RP-6306和RP-3500靶向CDK1活性是治疗ccne1扩增的OVCAs和EMCAs的有效治疗方法。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.