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 language | English (US) |
|---|---|
| Pages (from-to) | 6594-6610 |
| Number of pages | 17 |
| Journal | Clinical Cancer Research |
| Volume | 24 |
| Issue number | 24 |
| DOIs | |
| State | Published - Dec 15 2018 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
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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 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 journal › Article
}
TY - JOUR
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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UR - http://www.scopus.com/inward/citedby.url?scp=85058473822&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-18-1446
DO - 10.1158/1078-0432.CCR-18-1446
M3 - Article
C2 - 30181387
AN - SCOPUS:85058473822
VL - 24
SP - 6594
EP - 6610
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 24
ER -