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Cyclin E Overexpression Sensitizes Triple-Negative Breast Cancer to Wee1 Kinase Inhibition.
Chen, Xian; Low, Kwang-Huei; Alexander, Angela; Jiang, Yufeng; Karakas, Cansu; Hess, Kenneth R; Carey, Jason P W; Bui, Tuyen N; Vijayaraghavan, Smruthi; Evans, Kurt W; Yi, Min; Ellis, D Christian; Cheung, Kwok-Leung; Ellis, Ian O; Fu, Siqing; Meric-Bernstam, Funda; Hunt, Kelly K; Keyomarsi, Khandan.
Afiliación
  • Chen X; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. kkeyomar@mdanderson.org XChen11@mdanderson.org.
  • Low KH; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Alexander A; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Jiang Y; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Karakas C; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Hess KR; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Carey JPW; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Bui TN; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Vijayaraghavan S; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Evans KW; Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Yi M; Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Ellis DC; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Cheung KL; School of Medicine, University of Nottingham, Nottingham, United Kingdom.
  • Ellis IO; School of Medicine, University of Nottingham, Nottingham, United Kingdom.
  • Fu S; Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Meric-Bernstam F; Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Hunt KK; Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Keyomarsi K; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. kkeyomar@mdanderson.org XChen11@mdanderson.org.
Clin Cancer Res ; 24(24): 6594-6610, 2018 12 15.
Article en En | MEDLINE | ID: mdl-30181387
PURPOSE: Poor prognosis in triple-negative breast cancer (TNBC) is due to an aggressive phenotype and lack of biomarker-driven targeted therapies. Overexpression of cyclin E and phosphorylated-CDK2 are correlated with poor survival in patients with TNBC, and the absence of CDK2 desensitizes cells to inhibition of Wee1 kinase, a key cell-cycle regulator. We hypothesize that cyclin E expression can predict response to therapies, which include the Wee1 kinase inhibitor, AZD1775. EXPERIMENTAL DESIGN: Mono- and combination therapies with AZD1775 were evaluated in TNBC cell lines and multiple patient-derived xenograft (PDX) models with different cyclin E expression profiles. The mechanism(s) of cyclin E-mediated replicative stress were investigated following cyclin E induction or CRISPR/Cas9 knockout by a number of assays in multiple cell lines. RESULTS: Cyclin E overexpression (i) is enriched in TNBCs with high recurrence rates, (ii) sensitizes TNBC cell lines and PDX models to AZD1775, (iii) leads to CDK2-dependent activation of DNA replication stress pathways, and (iv) increases Wee1 kinase activity. Moreover, treatment of cells with either CDK2 inhibitors or carboplatin leads to transient transcriptional induction of cyclin E (in cyclin E-low tumors) and result in DNA replicative stress. Such drug-mediated cyclin E induction in TNBC cells and PDX models sensitizes them to AZD1775 in a sequential treatment combination strategy.Conclusions: Cyclin E is a potential biomarker of response (i) for AZD1775 as monotherapy in cyclin E-high TNBC tumors and (ii) for sequential combination therapy with CDK2 inhibitor or carboplatin followed by AZD1775 in cyclin E-low TNBC tumors.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Tirosina Quinasas / Proteínas Nucleares / Expresión Génica / Proteínas de Ciclo Celular / Resistencia a Antineoplásicos / Ciclina E / Inhibidores de Proteínas Quinasas / Neoplasias de la Mama Triple Negativas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Tirosina Quinasas / Proteínas Nucleares / Expresión Génica / Proteínas de Ciclo Celular / Resistencia a Antineoplásicos / Ciclina E / Inhibidores de Proteínas Quinasas / Neoplasias de la Mama Triple Negativas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos