Cyclin E-associated kinase activity predicts response to platinum-based chemotherapy.

Abstract

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.

• Authors: Isabelle Bedrosian, Christine Lee, Susan L Tucker, Shana L Palla, Karen Lu, Khandan Keyomarsi
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 13 Issue 16 Pg. 4800-6 (Aug 15 2007) ISSN: 1078-0432 [Print] United States
• PMID: 17699858 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Cyclin E
• Carboplatin
• Cyclin-Dependent Kinases
• Cisplatin

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (therapeutic use)
• Carboplatin (therapeutic use)
• Cisplatin (therapeutic use)
• Cyclin E (analysis, physiology)
• Cyclin-Dependent Kinases (metabolism)
• Female
• Humans
• Middle Aged
• Ovarian Neoplasms (chemistry, drug therapy, mortality)
• Proportional Hazards Models
• Retrospective Studies