| Autor: |
Xu, Haineng, George, Erin, Kinose, Yasuto, Kim, Hyoung, Shah, Jennifer B., Peake, Jasmine D., Ferman, Benjamin, Medvedev, Sergey, Murtha, Thomas, Barger, Carter J., Devins, Kyle M., D’Andrea, Kurt, Wubbenhorst, Bradley, Schwartz, Lauren E., Hwang, Wei-Ting, Mills, Gordon B., Nathanson, Katherine L., Karpf, Adam R., Drapkin, Ronny, Brown, Eric J., Simpkins, Fiona |
| Zdroj: |
Cell Reports Medicine; September 2021, Vol. 2 Issue: 9 |
| Abstrakt: |
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 CCNE1overexpression 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 CCNE1copy number (CN)-dependent manner. Only upon CCNE1induction 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 CCNE1CN is a clinically tractable biomarker predicting responsiveness to low-dose WEE1i-ATRi for aggressive subsets of OVCAs/EMCAs. |
| Databáze: |
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