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Cell Rep Med ; 2(9): 100394, 2021 09 21.
Article in English | MEDLINE | ID: mdl-34622231

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.


Subject(s)
Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors , Biomarkers, Tumor/genetics , Cell Cycle Proteins/antagonists & inhibitors , Cyclin E/genetics , Endometrial Neoplasms/genetics , Gene Dosage , Models, Biological , Oncogene Proteins/genetics , Ovarian Neoplasms/genetics , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Apoptosis , Ataxia Telangiectasia Mutated Proteins/metabolism , Biomarkers, Tumor/metabolism , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cell Survival/genetics , DNA Replication , Endometrial Neoplasms/pathology , Female , Humans , Mice, Inbred NOD , Mice, SCID , Ovarian Neoplasms/pathology , Protein-Tyrosine Kinases/metabolism , S Phase , Signal Transduction , Tumor Stem Cell Assay , Xenograft Model Antitumor Assays
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