Scholarlink

<p>Ovarian cancers (OVCAs) and endometrial cancers (EMCAs) with <i>CCNE1-</i>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 <i>CCNE1</i>-amplification. We hypothesize that <i>CCNE1</i>-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 <i>CCNE1</i>-amplified compared to non-amplified cells. Combination treatment produces durable antitumor activity, reduces metastasis and increases survival in <i>CCNE1</i>-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 <i>CCNE1</i>-dependent manner. These findings suggest that targeting CDK1 activity by combining RP-6306 with RP-3500 is an effective therapeutic approach to treat <i>CCNE1</i>-amplifed OVCAs and EMCAs.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月1日

查看全文
  • 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

摘要

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.