Skip to main content

Research Repository

Advanced Search

Cyclin E overexpression sensitizes triple negative breast cancer to Wee1 kinase Inhibition

Chen, Xian; Low, Kwang Hui; Alexander, Angela; Jiang, Yufeng; Karakas, Cansu; Hess, Kenneth R.; Carey, Jason P.W.; Bui, Tuyen; 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

Authors

Xian Chen

Kwang Hui Low

Angela Alexander

Yufeng Jiang

Cansu Karakas

Kenneth R. Hess

Jason P.W. Carey

Tuyen Bui

Smruthi Vijayaraghavan

Kurt W. Evans

Min Yi

D. Christian Ellis

Siqing Fu

Funda Meric-Bernstam

Kelly K. Hunt

Khandan Keyomarsi



Abstract

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 TNBC patients, 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 cells lines. Results: Cyclin E overexpression (1) is enriched in TNBCs with high recurrence rates, (2) sensitizes TNBC cell lines and PDX models to AZD1775, (3) leads to CDK2-dependent activation of DNA replication stress pathways and (4) 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 (1) for AZD1775 as monotherapy in cyclin E high TNBC tumors and (2) for sequential combination therapy with CDK2 inhibitor or carboplatin followed by AZD1775 in cyclin E low TNBC tumors.

Journal Article Type Article
Publication Date Sep 4, 2018
Journal Clinical Cancer Research
Print ISSN 1078-0432
Electronic ISSN 1557-3265
Publisher American Association for Cancer Research
Peer Reviewed Peer Reviewed
APA6 Citation Chen, X., Low, K. H., Alexander, A., Jiang, Y., Karakas, C., Hess, K. R., …Keyomarsi, K. (2018). Cyclin E overexpression sensitizes triple negative breast cancer to Wee1 kinase Inhibition. Clinical Cancer Research, doi:10.1158/1078-0432.ccr-18-1446
DOI https://doi.org/10.1158/1078-0432.ccr-18-1446
Keywords Cancer Research; Oncology
Publisher URL http://clincancerres.aacrjournals.org/content/early/2018/09/01/1078-0432.CCR-18-1446

Files





You might also like



Downloadable Citations

;