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Nutlin-3: A novel potential therapeutic in p53 wild-type ovarian carcinomas.
J Clin Oncol 30, 2012 (suppl; abstr e15583)
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
Background: Epithelial ovarian cancer (OC) is a molecularly and clinically heterogeneous disease, yet treatment is the same for all subtypes. Type I carcinomas, including low grade serous, mucinous, clear cell, and endometrioid OCs, are relatively chemoresistant. In contrast, Type II or high grade serous OCs are more aggressive yet responsive to chemotherapy. Molecularly, 96% of high grade serous OCs harbor p53 mutations, whereas Type I carcinomas are more frequently p53 wild-type. Nutlin-3 is a novel therapeutic which inhibits MDM2, activates wild-type p53, and induces apoptosis. We therefore sought to validate nutlin-3 as a therapeutic compound for p53 wild-type OCs. Methods: Two low grade serous, 2 clear cell, 2 endometrioid, 3 mucinous, and 4 high grade serous OC cell lines were treated with varying concentrations of nutlin-3, and proliferation assays were performed. A p53-null cell line was used as a negative control. The cells were then treated with nutlin-3 at their IC50s, and qRT-PCR and Western blot (WB) quantified MDM2, p53, and p21 expression at 24, 48, and 72 hours after treatment. The cell lines were sequenced for p53 mutations in exons 5-8. Results: Responses to nutlin-3 were variable and dependent on p53 mutation status. Low grade and clear cell lines were most sensitive to nutlin-3, endometrioid type were intermediately sensitive, and mucinous were resistant. Two of the four high grade cell lines were sensitive to nutlin-3, both of which were p53 wild-type. Endometrioid and low grade serous cell lines possessing heterozygous p53 mutations were still more sensitive than the p53-null cell line. On qRT-PCR and WB, levels of p53 were decreased after nutlin-3 treatment and were absent in the p53-null cell line. MDM2 and p21 were initially upregulated in sensitive cell lines, but returned to near-baseline levels after 72 hours. In the more resistant cell lines, p21 induction was reduced or absent. Conclusions: Nutlin-3 is a novel potential therapeutic agent for p53 wild-type ovarian carcinoma, and is dependent on an intact p53 pathway with p21 upregulation. Even OC cell lines with heterozygous p53 mutation responded modestly to nutlin-3 treatment. Further investigation of nutlin-3 treatment in ovarian cancer is warranted.
Presentations by Erin Rebecca King:
Regulation of the tumor suppressor gene PAEP in the transition from serous borderline ovarian tumors to low-grade serous ovarian carcinomas.Session: Gynecologic Cancer (General Poster Session)