CCNE1-amplified ovarian cancers (OVCAs) and endometrial cancers (EMCAs) are associated with platinum resistance and poor survival, representing a clinically unmet need. We hypothesized that dysregulated cell-cycle progression promoted by CCNE1 overexpression would lead to increased sensitivity to low-dose WEE1 inhibition and ataxia telangiectasia and Rad3-related (ATR) inhibition (WEE1i-ATRi), thereby optimizing efficacy and tolerability. The addition of ATRi to WEE1i is required to block feedback activation of ATR signaling mediated by WEE1i. Low-dose WEE1i-ATRi synergistically decreases viability and colony formation and increases replication fork collapse and double-strand breaks (DSBs) in a CCNE1 copy number (CN)-dependent manner. Only upon CCNE1 induction does WEE1i perturb DNA synthesis at S-phase entry, and addition of ATRi increases DSBs during DNA synthesis. Inherent resistance to WEE1i is overcome with WEE1i-ATRi, with notable durable tumor regressions and improved survival in patient-derived xenograft (PDX) models in a CCNE1-level-dependent manner. These studies demonstrate that CCNE1 CN is a clinically tractable biomarker predicting responsiveness to low-dose WEE1i-ATRi for aggressive subsets of OVCAs/EMCAs.

CCNE1扩增的卵巢癌 (OVCA) 和子宫内膜癌 (EMCA) 与铂类耐药和生存率低相关，代表了临床上未满足的需求。我们假设CCNE1过表达促进的细胞周期进程失调会导致对低剂量 WEE1 抑制、共济失调毛细血管扩张和 Rad3 相关 (ATR) 抑制 (WEE1i-ATRi) 的敏感性增加，从而优化疗效和耐受性。需要向 WEE1i 添加 ATRi 来阻止 WEE1i 介导的 ATR 信号反馈激活。低剂量 WEE1i-ATRi 以CCNE1拷贝数 (CN) 依赖性方式协同降低活力和集落形成，并增加复制叉塌陷和双链断裂 (DSB)。仅在CCNE1诱导后，WEE1i 才会扰乱进入 S 期的 DNA 合成，并且添加 ATRi 会增加 DNA 合成过程中的 DSB。 WEE1i-ATRi 克服了对 WEE1i 的固有耐药性，以CCNE1水平依赖性方式，在患者来源的异种移植 (PDX) 模型中实现了显着的持久肿瘤消退并提高了生存率。这些研究表明， CCNE1 CN 是一种临床上易于处理的生物标志物，可预测 OVCA/EMCA 侵袭性子集对低剂量 WEE1i-ATRi 的反应性。