Journal
CELL REPORTS MEDICINE
Volume 2, Issue 9, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.xcrm.2021.100394
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Funding
- Mary Kay Foundation [017-64]
- Rivkin Center for Ovarian Cancer
- Ovarian Cancer Research Alliance [600095, 545152]
- AACR-AstraZeneca Ovarian Cancer Research Fellowship
- NIH [5R37CA215436-02, 5R01CA189743]
- Kaleidoscope of Hope
- George and Emily McMichael Harrison Grant
- NCI [CA217685, CA217842, CA098258]
- [5-K12-HD-001265-20]
- [3-K12HD-000849-34S1]
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Ovarian and endometrial cancers with CCNE1 amplification are associated with platinum resistance and poor survival outcomes. Targeting dysregulated cell cycle progression with low-dose WEE1 inhibition and ATR inhibition synergistically decreases cell viability and increases DNA damage, providing a potential therapeutic strategy for these aggressive subsets of cancers.
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.
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