Mutant p53: A Novel Target for the Treatment of Patients with Triple-Negative Breast Cancer?

Abstract

The identification and validation of a targeted therapy for patients with triple-negative breast cancer (TNBC) is currently one of the most urgent needs in breast cancer therapeutics. One of the key reasons for the failure to develop a new therapy for this subgroup of breast cancer patients has been the difficulty in identifying a highly prevalent, targetable molecular alteration in these tumors. Recently however, the p53 gene was found to be mutated in approximately 80% of basal/TNBC, raising the possibility that targeting the mutant p53 protein product might be a new approach for the treatment of this form of breast cancer. In this study, we investigated the anti-cancer activity of PRIMA-1 and PRIMA-1^MET (APR-246), two compounds which were previously reported to reactivate mutant p53 and convert it to a form with wild-type (WT) properties. Using a panel of 18 breast cancer cell lines and 2 immortalized breast cell lines, inhibition of proliferation by PRIMA-1 and PRIMA-1^MET was found to be cell-line dependent, but independent of cell line molecular subtype. Although response was independent of molecular subtype, p53 mutated cell lines were significantly more sensitive to PRIMA-1^MET than p53 WT cells (p=0.029). Furthermore, response (measured as IC₅₀ value) correlated significantly with p53 protein level as measured by ELISA (p=0.0089, r=-0.57, n=19). In addition to inhibiting cell proliferation, PRIMA-1^MET induced apoptosis and inhibited migration in a p53 mutant-dependent manner. Based on our data, we conclude that targeting mutant p53 with PRIMA-1^MET is a potential new approach for treating p53-mutated breast cancer, including the subgroup with triple-negative (TN) disease. This article is protected by copyright. All rights reserved.

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