Cyclin E overexpression sensitizes triple-negative breast cancer to Wee1 kinase inhibition

Xian Chen, Kwang Huei Low, Angela Alexander, Yufeng Jiang, Cansu Karakas, Kenneth R Hess, Jason Patrick Carey, Tuyen N. Bui, Smruthi Vijayaraghavan, Kurt W. Evans, Min Yi, D. Christian Ellis, Kwok Leung Cheung, Ian O. Ellis, Siqing Fu, Funda Meric-Bernstam, Kelly K Hunt, Khandan Keyomarsi

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)6594-6610
Number of pages17
JournalClinical Cancer Research
Volume24
Issue number24
DOIs
StatePublished - Dec 15 2018

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Triple Negative Breast Neoplasms
Cyclin E
Phosphotransferases
Cyclins
Heterografts
Carboplatin
Cell Line
Therapeutics
Clustered Regularly Interspaced Short Palindromic Repeats
Biomarkers
Breast Neoplasms
DNA Replication
MK 1775
Cell Cycle
Research Design
Phenotype
Recurrence
Survival
DNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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 Patrick; 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.

In: Clinical Cancer Research, Vol. 24, No. 24, 15.12.2018, p. 6594-6610.

Research output: Contribution to journalArticle

Chen, X, Low, KH, Alexander, A, Jiang, Y, Karakas, C, Hess, KR, Carey, JP, Bui, TN, Vijayaraghavan, S, Evans, KW, Yi, M, Ellis, DC, Cheung, KL, Ellis, IO, Fu, S, Meric-Bernstam, F, Hunt, KK & Keyomarsi, K 2018, 'Cyclin E overexpression sensitizes triple-negative breast cancer to Wee1 kinase inhibition', Clinical Cancer Research, vol. 24, no. 24, pp. 6594-6610. https://doi.org/10.1158/1078-0432.CCR-18-1446
Chen, Xian ; Low, Kwang Huei ; Alexander, Angela ; Jiang, Yufeng ; Karakas, Cansu ; Hess, Kenneth R ; Carey, Jason Patrick ; 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. / Cyclin E overexpression sensitizes triple-negative breast cancer to Wee1 kinase inhibition. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 24. pp. 6594-6610.
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title = "Cyclin E overexpression sensitizes triple-negative breast cancer to Wee1 kinase inhibition",
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 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.",
author = "Xian Chen and Low, {Kwang Huei} and Angela Alexander and Yufeng Jiang and Cansu Karakas and Hess, {Kenneth R} and Carey, {Jason Patrick} and Bui, {Tuyen N.} and Smruthi Vijayaraghavan and Evans, {Kurt W.} and Min Yi and Ellis, {D. Christian} and Cheung, {Kwok Leung} and Ellis, {Ian O.} and Siqing Fu and Funda Meric-Bernstam and Hunt, {Kelly K} and Khandan Keyomarsi",
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T1 - Cyclin E overexpression sensitizes triple-negative breast cancer to Wee1 kinase inhibition

AU - Chen, Xian

AU - Low, Kwang Huei

AU - Alexander, Angela

AU - Jiang, Yufeng

AU - Karakas, Cansu

AU - Hess, Kenneth R

AU - Carey, Jason Patrick

AU - Bui, Tuyen N.

AU - Vijayaraghavan, Smruthi

AU - Evans, Kurt W.

AU - Yi, Min

AU - Ellis, D. Christian

AU - Cheung, Kwok Leung

AU - Ellis, Ian O.

AU - Fu, Siqing

AU - Meric-Bernstam, Funda

AU - Hunt, Kelly K

AU - Keyomarsi, Khandan

PY - 2018/12/15

Y1 - 2018/12/15

N2 - 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.

AB - 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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