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通过联合抑制PKMYT1和ATR靶向扩增的卵巢癌和子宫内膜癌。

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

作者信息

Xu Haineng, George Erin, Gallo David, Medvedev Sergey, Wang Xiaolei, Kryczka Rosie, Hyer Marc L, Fourtounis Jimmy, Stocco Rino, Aguado-Fraile Elia, Petrone Adam, Yin Shou Yun, Shiwram Ariya, Anderson Matthew, Kim Hyoung, Liu Fang, Marshall C Gary, Simpkins Fiona

机构信息

Penn Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA.

出版信息

Res Sq. 2024 Feb 16:rs.3.rs-3854682. doi: 10.21203/rs.3.rs-3854682/v1.

DOI:10.21203/rs.3.rs-3854682/v1
PMID:38410486
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10896384/
Abstract

Ovarian cancers (OVCAs) and endometrial cancers (EMCAs) with amplification are often resistant to standard of care treatment and represent an unmet clinical need. Previously, synthetic-lethal screening identified loss of the CDK1 regulator, PKMYT1, as synthetically lethal with -amplification. We hypothesized that -amplification associated replication stress will be more effectively targeted by combining the PKMYT1 inhibitor, lunresertib (RP-6306), with the ATR inhibitor, camonsertib (RP-3500/RG6526). Low dose combination RP-6306 with RP-3500 synergistically increased cytotoxicity more in amplified compared to non-amplified cells. Combination treatment produced durable antitumor activity and increased survival in amplified patient-derived and cell line-derived 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 -dependent manner. These findings suggest that targeting CDK1 activity by combining RP-6306 with RP-3500 is a novel therapeutic approach to treat -amplifed OVCAs and EMCAs.

摘要

具有扩增的卵巢癌（OVCAs）和子宫内膜癌（EMCAs）通常对标准治疗产生耐药性，代表了一种未满足的临床需求。此前，合成致死筛选确定CDK1调节因子PKMYT1的缺失与扩增具有合成致死性。我们假设，通过将PKMYT1抑制剂伦瑞替尼（RP - 6306）与ATR抑制剂卡蒙替尼（RP - 3500/RG6526）联合使用，与扩增相关的复制应激将得到更有效的靶向治疗。与未扩增细胞相比，低剂量的RP - 6306与RP - 3500联合使用在扩增细胞中更能协同增加细胞毒性。联合治疗在扩增的患者来源和细胞系来源的异种移植模型中产生了持久的抗肿瘤活性并延长了生存期。从机制上讲，低剂量的RP - 6306与RP - 3500联合使用比单一疗法更能增加CDK1的激活，以依赖的方式触发快速且强烈的过早有丝分裂、DNA损伤和细胞凋亡。这些发现表明，将RP - 6306与RP - 3500联合使用靶向CDK1活性是治疗扩增型OVCAs和EMCAs的一种新的治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4787/10896384/c5d5baeacd9f/nihpp-rs3854682v1-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4787/10896384/d95583f283e0/nihpp-rs3854682v1-f0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4787/10896384/c5d5baeacd9f/nihpp-rs3854682v1-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4787/10896384/d95583f283e0/nihpp-rs3854682v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4787/10896384/ac6c9aba1e73/nihpp-rs3854682v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4787/10896384/ffc8e45624b5/nihpp-rs3854682v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4787/10896384/14fa69a66123/nihpp-rs3854682v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4787/10896384/32f7cc77bb1b/nihpp-rs3854682v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4787/10896384/b4cf55ab90df/nihpp-rs3854682v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4787/10896384/c5d5baeacd9f/nihpp-rs3854682v1-f0007.jpg

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