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

• DOI: 10.1016/j.xcrm.2021.100394
• Publication Date: 2021-09-23T23:14:38Z
• Authors: 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. Nath...; Adam R. Karpf; Ronny Drapkin; Eric J. Brown; Fiona Simpkins
• Keywords: DNA Replication; CCNE1 copy number; Medicine (General); Cell Survival; Gene Dosage; Apoptosis; Cell Cycle Proteins; Ataxia Telangiectasia Mutated Proteins; Mice, SCID; Models, Biological; Article; S Phase; 03 medical and health sciences; R5-920; Mice, Inbred NOD; Cell Line, Tumor; Cyclin E; Biomarkers, Tumor; Animals; Humans; WEE1; Oncogene Proteins; Ovarian Neoplasms; 0303 health sciences; Protein-Tyrosine Kinases; ovarian and endometrial cancer; Endometrial Neoplasms; 3. Good health; ATR; biomarker; Female

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.