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-1MET (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-1MET 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-1MET 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-1MET induced apoptosis and inhibited migration in a p53 mutant-dependent manner. Based on our data, we conclude that targeting mutant p53 with PRIMA-1MET is a potential new approach for treating p53-mutated breast cancer, including the subgroup with triple-negative (TN) disease.

• Authors: N C Synnott, A Murray, P M McGowan, M Kiely, P A Kiely, N O'Donovan, D P O'Connor, W M Gallagher, J Crown, M J Duffy
• Journal: International journal of cancer (Int J Cancer) Vol. 140 Issue 1 Pg. 234-246 (Jan 01 2017) ISSN: 1097-0215 [Electronic] United States
• PMID: 27615392 (Publication Type: Journal Article)
• Copyright: © 2016 UICC.

Chemical References

• Aza Compounds
• Bridged Bicyclo Compounds, Heterocyclic
• Quinuclidines
• TP53 protein, human
• Tumor Suppressor Protein p53
• 2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one
• eprenetapopt

Topics

• Aza Compounds (pharmacology)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Molecular Targeted Therapy
• Mutation (drug effects)
• Quinuclidines (pharmacology)
• Triple Negative Breast Neoplasms (drug therapy, genetics, metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)