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

Haineng Xu, Erin George, Yasuto Kinose, Hyoung Kim, Jennifer B. Shah, Jasmine D. Peake, Benjamin Ferman, Sergey Medvedev, Thomas Murtha, Carter J. Barger, Kyle M. Devins, Kurt D'Andrea, Bradley Wubbenhorst, Lauren E. Schwartz, Wei Ting Hwang, Gordon B. Mills, Katherine L. Nathanson, Adam R. Karpf, Ronny Drapkin, Eric J. BrownFiona Simpkins

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number100394
JournalCell Reports Medicine
Volume2
Issue number9
DOIs
StatePublished - Sep 21 2021

Keywords

  • ATR
  • CCNE1 copy number
  • WEE1
  • biomarker
  • ovarian and endometrial cancer

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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