Details

Autor(en) / Beteiligte

• 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

Titel

CCNE1 copy number is a biomarker for response to combination WEE1-ATR inhibition in ovarian and endometrial cancer models

Ist Teil von

• Cell reports. Medicine, 2021-09, Vol.2 (9), p.100394, Article 100394

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• 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. [Display omitted] CCNE1 induction increases ATR signaling and sensitivity to WEE1i-ATRi treatmentWEE1i-ATRi increases tumor regression in a CCNE1-level-dependent manner in PDXsDifferential molecular effects of WEE1i and ATRi promote replication fork collapseCCNE1 amplification is a reliable biomarker predictive of response to WEE1i-ATRi CCNE1 amplification is associated with platinum resistance and poor survival in ovarian and endometrial cancers. Xu et al. identify CCNE1 overexpression as a sensitizer to combination WEE1 and ATR inhibition that allows lower-dosing strategies to decrease toxicity, thus identifying a new treatment for patients with limited options.