Mutant p53: a novel target for the treatment of patients with triple-negative breast cancer?
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-1METwas 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-1METthan p53 WT cells (p = 0.029). Furthermore, response (measured as IC50value) 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-1METinduced apoptosis and inhibited migration in a p53 mutant-dependent manner. Based on our data, we conclude that targeting mutant p53 with PRIMA-1METis a potential new approach for treating p53-mutated breast cancer, including the subgroup with triple-negative (TN) disease.
UCD School of Medicine and Medical Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
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http://orcid.org/0000-0001-8331-1143
NC
Synnott
UCD School of Medicine and Medical Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
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A
Murray
UCD School of Medicine and Medical Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
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PM
McGowan
Department of Life Sciences, University of Limerick, Limerick, Ireland.
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M
Kiely
Department of Life Sciences, University of Limerick, Limerick, Ireland.
P A
PA
Kiely
National Institute for Cellular Biotechnology (NICB), Dublin City University, Dublin, Ireland.
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N
O'Donovan
Department of Molecular & Cellular Therapeutics, Royal College of Surgeons Ireland, Dublin, Ireland.
D P
DP
O'Connor
UCD School of Biomolecular and Biomedical Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
W M
WM
Gallagher
Department of Medical Oncology, St Vincent's University Hospital, Dublin, Ireland.
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J
Crown
UCD School of Medicine and Medical Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.|UCD Clinical Research Centre, St. Vincent's University Hospital, Dublin, Ireland.
M J
MJ
Duffy
D001372:Aza Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation / Q000187:drug effects; D011812:Quinuclidines / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011812:Quinuclidines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C451219:2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one; C533410:eprenetapopt
APR-246; PRIMA-1MET; breast cancer; mutant p53; triple-negative breast cancer