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Cyclin E–Associated Kinase Activity Predicts Response to Platinum-Based Chemotherapy

Authors' Affiliations: Departments of ¹ Surgical Oncology, ² Gynecologic Oncology, ³ Bioinformatics and Computational Biology, and ⁴ Experimental Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Khandan Keyomarsi, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 066, Houston, TX 77030. Phone: 713-792-4845; Fax: 713-794-5369; E-mail: kkeyomar{at}mdanderson.org.

Purpose: The role of cyclin E as a predictive marker of response to chemotherapy remains unknown. We have previously shown that deregulation of cyclin E in an ovarian tumor cell line model enhances cyclin E–associated kinase activity and sensitizes tumor cells to cisplatinum. We hypothesized that cyclin E deregulation would predict for responsiveness to platinum-based regimens in ovarian cancer patients.

Experimental Design: Patients who met the following criteria were retrospectively identified from the institutional tumor bank records: (a) high-grade ovarian epithelial malignancy, (b) stage III/stage IV disease, (c) optimally debulked, (d) completed platinum-based therapy. Tumor samples were analyzed for cyclin E, p21, and p27 by Western blot analysis and assessed for cyclin E–associated kinase activity.

Results: Seventy-five patients, who met the study criteria, were identified. Cyclin E protein levels did not correlate with cyclin E–cdk2 kinase activity (Spearman's rho, 0.07; P = 0.58). Cyclin E–associated kinase activity was the only significant predictive marker for response to platinum-based therapy, with higher response rates seen in patients with higher levels of activity (P = 0.045). Cyclin E protein levels did not predict for platinum sensitivity (P = 0.20). In contrast, cyclin E protein levels, but not cyclin E–associated kinase activity, was a significant predictor for freedom from recurrence (P = 0.01 and P = 0.25, respectively).

Conclusions: Cyclin E overexpression and cyclin E–associated kinase activity have distinct roles in predicting for response to chemotherapy and outcome in ovarian cancer patients. These results suggest a compartmentalization of cyclin E functions in the oncogenic process.