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Cell Rep Med ; 2(9): 100394, 2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34622231

RESUMO

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.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Biomarcadores Tumorais/genética , Proteínas de Ciclo Celular/antagonistas & inibidores , Ciclina E/genética , Neoplasias do Endométrio/genética , Dosagem de Genes , Modelos Biológicos , Proteínas Oncogênicas/genética , Neoplasias Ovarianas/genética , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Apoptose , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Biomarcadores Tumorais/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Replicação do DNA , Neoplasias do Endométrio/patologia , Feminino , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Ovarianas/patologia , Proteínas Tirosina Quinases/metabolismo , Fase S , Transdução de Sinais , Ensaio Tumoral de Célula-Tronco , Ensaios Antitumorais Modelo de Xenoenxerto
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