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


METHODS
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.
Bedrosian
Isabelle
I
Department of Surgical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Lee
Christine
C
Tucker
Susan L
SL
Palla
Shana L
SL
Lu
Karen
K
Keyomarsi
Khandan
K
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016190:Carboplatin / Q000627:therapeutic use*; D002945:Cisplatin / Q000627:therapeutic use*; D019927:Cyclin E / Q000032:analysis / Q000502:physiology*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality; D016016:Proportional Hazards Models; D012189:Retrospective Studies
D000970:Antineoplastic Agents; D019927:Cyclin E; D016190:Carboplatin; D018844:Cyclin-Dependent Kinases; D002945:Cisplatin