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

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.

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, https://doi.org/10.1158/1078-0432.ccr-18-1446

• Journal Article Type: Article
• Acceptance Date: Aug 29, 2018
• Online Publication Date: Sep 4, 2018
• Publication Date: Sep 4, 2018
• Deposit Date: Oct 10, 2018
• Publicly Available Date: Sep 5, 2019
• Journal: Clinical Cancer Research
• Print ISSN: 1078-0432
• Electronic ISSN: 1557-3265
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1158/1078-0432.ccr-18-1446
• Keywords: Cancer Research; Oncology
• Public URL: https://nottingham-repository.worktribe.com/output/1156956
• Publisher URL: http://clincancerres.aacrjournals.org/content/early/2018/09/01/1078-0432.CCR-18-1446
• Contract Date: Oct 10, 2018