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Cyclin E Overexpression Sensitizes Triple- Negative Breast Cancer To Published OnlineFirst September 4, 2018; DOI: 10.1158/1078-0432.CCR-18-1446 Translational Cancer Mechanisms and Therapy Clinical Cancer Research Cyclin E Overexpression Sensitizes Triple- Negative Breast Cancer to Wee1 Kinase Inhibition Xian Chen1, Kwang-Huei Low1, Angela Alexander1, Yufeng Jiang1, Cansu Karakas1, Kenneth R. Hess2, Jason P.W. Carey1, Tuyen N. Bui1, Smruthi Vijayaraghavan1, Kurt W. Evans3, Min Yi4, D. Christian Ellis1, Kwok-Leung Cheung5, Ian O. Ellis5, Siqing Fu3, Funda Meric-Bernstam3, Kelly K. Hunt4, and Khandan Keyomarsi1 Abstract Purpose: Poor prognosis in triple-negative breast cancer Results: Cyclin E overexpression (i) is enriched in TNBCs (TNBC) is due to an aggressive phenotype and lack of with high recurrence rates, (ii) sensitizes TNBC cell lines and biomarker-driven targeted therapies. Overexpression of PDX models to AZD1775, (iii) leads to CDK2-dependent cyclin E and phosphorylated-CDK2 are correlated with poor activation of DNA replication stress pathways, and (iv) survival in patients with TNBC, and the absence of CDK2 increases Wee1 kinase activity. Moreover, treatment of cells desensitizes cells to inhibition of Wee1 kinase, a key cell- with either CDK2 inhibitors or carboplatin leads to transient cycle regulator. We hypothesize that cyclin E expression can transcriptional induction of cyclin E (in cyclin E–low tumors) predict response to therapies, which include the Wee1 and result in DNA replicative stress. Such drug-mediated cyclin kinase inhibitor, AZD1775. E induction in TNBC cells and PDX models sensitizes them to Experimental Design: Mono- and combination therapies AZD1775 in a sequential treatment combination strategy. with AZD1775 were evaluated in TNBC cell lines and multiple Conclusions: Cyclin E is a potential biomarker of patient-derived xenograft (PDX) models with different cyclin E response (i) for AZD1775 as monotherapy in cyclin E–high expression profiles. The mechanism(s) of cyclin E–mediated TNBC tumors and (ii) for sequential combination replicative stress were investigated following cyclin E induc- therapy with CDK2 inhibitor or carboplatin followed by tion or CRISPR/Cas9 knockout by a number of assays in AZD1775 in cyclin E–low TNBC tumors. Clin Cancer Res; 24(24); multiple cell lines. 6594–610. Ó2018 AACR. Introduction 50% of patients with TNBC will achieve complete pathologic response (pCR) to standard therapy, there are no biomarkers to Triple-negative breast cancer (TNBC) is a subtype of invasive select those from the patients who need other targeted breast cancer that lacks estrogen receptor, progesterone recep- approaches. As a result, patients with TNBC have a higher tor, and HER2 expression (1). TNBC accounts for up to 17% of likelihood of developing recurrence within the first 5 years of breast cancers and represents an aggressive phenotype with follow-up mainly due to lack of specific targets (2, 3). higher histologic grade, larger tumor size, and more advanced Over 60% of TNBCs harbor TP53 mutations (4–6) and the stage at diagnosis, and more likely to affect younger women cell cycle of these tumors is deregulated at the G –S and G –M and African-American women. Patients with TNBC have 1 2 checkpoints. This deregulation often leads to defects in DNA decreased overall survival compared with patients with other repair pathways, whose proper function is required to respond breast cancer subtypes. This decreased survival is due in part to to DNA replicative stress (7, 8). Exploiting the machinery that the lack of targeted therapies for TNBCs. While about 40%– regulates cell-cycle checkpoints and DNA repair for cancer therapy has been the focus of numerous investigations; how- ever, translation to patient care has not been very successful. 1Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 2Department of Biostatistics, The A key challenge has been the lack of consistent and validated University of Texas MD Anderson Cancer Center, Houston, Texas. 3Department predictive biomarkers that can readily identify tumors likely of Investigational Cancer Therapeutics, The University of Texas MD Anderson to respond to inhibitors of the DNA repair pathways, specif- Cancer Center, Houston, Texas. 4Department of Breast Surgical Oncology, The ically those that target DNA replicative stress. One such inhib- 5 University of Texas MD Anderson Cancer Center, Houston, Texas. School of itor, AZD1775, targets Wee1 kinase, a key regulator of the Medicine, University of Nottingham, Nottingham, United Kingdom. G2–M checkpoint that negatively regulates entry into mitosis Note: Supplementary data for this article are available at Clinical Cancer through inactivation of CDK1, arresting cells in G2–Mand Research Online (http://clincancerres.aacrjournals.org/). allowing for DNA repair (9). Wee1 kinase inhibition abrogates Corresponding Authors: Khandan Keyomarsi, The University of Texas MD the G2–M arrest leading to premature mitosis and also dereg- Anderson Cancer Center, 6565 MD Anderson Blvd., Unit 1035, Houston, TX, ulates DNA replication at S-phase leading to DNA damage. 77030. Phone: 713-792-4845; Fax: 713-794-5369; E-mail: (10–13). Cells with DNA replicative stress are therefore vul- [email protected]; and Xian Chen, [email protected] nerable to Wee1 kinase inhibition (14). Although AZD1775 doi: 10.1158/1078-0432.CCR-18-1446 has been proposed for treatment of TP53-defective cancers Ó2018 American Association for Cancer Research. (15, 16), studies have shown that the therapeutic efficacy of 6594 Clin Cancer Res; 24(24) December 15, 2018 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst September 4, 2018; DOI: 10.1158/1078-0432.CCR-18-1446 Overexpressed Cyclin E Sensitizes TNBC to Wee1 Inhibition from the ATCC and cultured as described previously (30, 40). Translational Relevance The TNBC cell lines SUM149 and SUM159 were obtained from TNBC is a subtype of invasive breast cancer with an aggres- Asterand Bioscience and cultured in Ham F12 medium with sive phenotype that has decreased survival compared with 5% FBS, 5 mg/mL insulin, and 1 mg/mL hydrocortisone. All other types of breast cancers due, in part, to the lack of cells were free of Mycoplasma contamination. Cell lines were biomarker-driven targeted therapies. Here we show that regularly (every 6 months) authenticated by karyotype and TNBCs can be separated into cyclin E–high or -low tumors short tandem repeat analysis at the MD Anderson Cancer Center and those with high cyclin E have a significantly worse prog- Characterized Cell Line Core facility. nosis. We show that cyclin E–high tumors are very sensitive to Wee1 kinase inhibition by AZD1775 as monotherapy. To Mouse and in vivo studies this end, we report on the relationship between cyclin E levels All animal studies were approved by the MD Anderson and the sensitivity to Wee1 kinase inhibition providing Institutional Animal Care and Use Committee and strictly the mechanistic evidence in support of a new clinical trial followed the recommendations in the Guide for the Care and (NCT03253679). We also identified cyclin E as a potential Use of Laboratory Animals from the NIH (Bethesda, MD). The predictor of response for the sequential combination therapy generation and preparation of patient-derived xenograft with a CDK2 inhibitor or carboplatin followed by AZD1775 (PDX) models were described in the Supplementary Methods in cyclin E–low tumors, providing the scientific rationale as reported previously (41). A total of 4 Â 106 SUM149 or for future biomarker-driven clinical trials in TNBC. MDA231 cells were injected into the mammary fat pad to generate xenograft models. The mice were given 50 mg/kg AZD1775 (prepared in 0.5 w/v% methyl cellulose 400 Solution) orally or 25 mg/kg dinaciclib (prepared in 20% Wee1 inhibition is independent of TP53 status (11, 17, 18), (2-hydroxypropyl)-b-cyclodextrin) or 30 mg/kg carboplatin (prepared in sterile water) by intraperitoneal injection. The suggesting alternative pathways that can deregulate G1–Stran- sition (19). In a recent phase I study with AZD1775, none of the length and width of tumor xenografts were measured by patients with a documented TP53 mutation exhibited a caliper twice per week and the volume of tumor was calculated ¼ Â 2 fi response to this agent (20). Given the complex regulation of by the formula volume length (width) /2. The speci c cell-cycle checkpoints, these seemingly contradictory results are treatment conditions for each experiment are provided in not unexpected, indicating alternative pathways that can dereg- Supplementary Methods. ulate the cell cycle and biomarkers are needed to help predict response to Wee1 kinase inhibition. High-throughput survival assay Cells were treated and their survival examined in 96-well plates Cyclin E, the key regulator of the G1–S transition, activates CDK2 to progress through the S-phase and promote DNA repli- over an 11-day period, a method that allows analysis of cytotox- cation (21, 22). Cyclin E levels are tightly cell-cycle regulated, with icity of one or more drugs in a wide range of adherent cell lines and provides results that are highly consistent with classic clonogenic peak CDK2-associated kinase activity occurring at the G1–S boundary in normally proliferating cells and tissues (23). Cyclin assays as described previously (40, 42). At the end of the 11-day E overexpression has been observed in a broad spectrum of assay, the plates were subjected to an MTT (3-(4, 5-dimethylthiazol- human malignancies, including breast cancer, and is associated 2-yl)-2, 5-diphenyltetrazolium bromide; RPI Corp.) assay as with poor outcomes (24–31). Overexpression of cyclin E dereg- described previously (40, 42). MTT was solubilized, and the absorbance of each well was read at 590 nm using an Epoch ulates the cell cycle at both G1–S and G2–M transitions by accelerating S-phase entry (32), affecting centrosome amplifica- microplate spectrophotometer (BioTek). The combination index tion (33) and stimulating premature mitosis (34, 35).
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