@article{3082b456929d47ffa8bff6ad001c14a5,
title = "CCNE1 copy number is a biomarker for response to combination WEE1-ATR inhibition in ovarian and endometrial cancer models",
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.",
keywords = "ATR, CCNE1 copy number, WEE1, biomarker, ovarian and endometrial cancer",
author = "Haineng Xu and Erin George and Yasuto Kinose and Hyoung Kim and Shah, {Jennifer B.} and Peake, {Jasmine D.} and Benjamin Ferman and Sergey Medvedev and Thomas Murtha and Barger, {Carter J.} and Devins, {Kyle M.} and Kurt D'Andrea and Bradley Wubbenhorst and Schwartz, {Lauren E.} and Hwang, {Wei Ting} and Mills, {Gordon B.} and Nathanson, {Katherine L.} and Karpf, {Adam R.} and Ronny Drapkin and Brown, {Eric J.} and Fiona Simpkins",
note = "Funding Information: The authors thank Mei Zheng for immunohistochemistry staining. This work was supported by the Mary Kay Foundation ( 017-64 to F.S.), Rivkin Center for Ovarian Cancer (to F.S. and E.G.), Ovarian Cancer Research Alliance ( 600095 to H.X. and 545152 to G.B.M.), AACR-AstraZeneca Ovarian Cancer Research Fellowship (to E.G.), NIH ( 5R37CA215436-02 to F.S. and 5R01CA189743 to E.J.B.), Kaleidoscope of Hope (to F.S.), George and Emily McMichael Harrison Grant (to E.G.), 5-K12-HD-001265-20 (to E.G.), 3-K12-HD-000849-34S1 (to E.G.), NCI ( CA217685 , CA217842 , and CA098258 to G.B.M.), and a gift from the Miriam and Sheldon G. Adelson Medical Research Foundation (to G.B.M. and R.D.). Funding Information: The authors thank Mei Zheng for immunohistochemistry staining. This work was supported by the Mary Kay Foundation (017-64 to F.S.), Rivkin Center for Ovarian Cancer (to F.S. and E.G.), Ovarian Cancer Research Alliance (600095 to H.X. and 545152 to G.B.M.), AACR-AstraZeneca Ovarian Cancer Research Fellowship (to E.G.), NIH (5R37CA215436-02 to F.S. and 5R01CA189743 to E.J.B.), Kaleidoscope of Hope (to F.S.), George and Emily McMichael Harrison Grant (to E.G.), 5-K12-HD-001265-20 (to E.G.), 3-K12-HD-000849-34S1 (to E.G.), NCI (CA217685, CA217842, and CA098258 to G.B.M.), and a gift from the Miriam and Sheldon G. Adelson Medical Research Foundation (to G.B.M. and R.D.). H.X. E.G. and F.S. designed the study, analyzed the data, and drafted the manuscript. H.X. and E.G. performed in vitro experiments. H.X. S.M. E.G. Y.K. B.F. T.M. and H.K. did the animal experiments. J.D.P. performed PCNA experiments. C.J.B. and A.R.K. generated FT282 Dox-inducible cell models. K.M.D. and L.E.S. quantified the immunohistochemistry data. J.B.S. K.D. B.W. and K.L.N. performed the next-generation DNA sequencing and analyzed the data. G.B.M. carried out the proteomic assay. R.D. established the FT282 cells. F.S. E.J.B. G.B.M. R.D. and W.-T.H. interpreted the data and revised the manuscript. H.X. and E.G. are co-first authors based on their equal contributions. All authors read and approved the manuscript. F.S. serves on a scientific advisory board and has received funding for clinical trials from AstraZeneca. G.B.M. receives support or acts as a consultant for AstraZeneca, ImmunoMET, Ionis, Nanostring, PDX Pharmaceuticals, Signalchem Lifesciences, Symphogen, Abbvie, Amphista, Ellipses Pharma, Eli Lilly, Medacorp, Turbine, Zentalis Pharmaceuticals, and Tarveda and has transferred technology to Myriad and Nanostring. E.J.B. serves on the scientific advisory board of Atrin Pharmaceuticals and has been an advisor for Sierra Oncology. R.D. serves on the scientific advisory board of Repare Therapeutics and Siamab Therapeutics and advises Mersana Therapeutics and nVision Medical. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = sep,
day = "21",
doi = "10.1016/j.xcrm.2021.100394",
language = "English (US)",
volume = "2",
journal = "Cell Reports Medicine",
issn = "2666-3791",
publisher = "Cell Press",
number = "9",
}