Mutant p53 as a therapeutic target for the treatment of triple-negative breast cancer: Prelinical investigation with the anti-p53 drug, APR-246.

卡铂 三阴性乳腺癌 多西紫杉醇 医学 乳腺癌 IC50型 免疫印迹 癌症研究 MTT法 细胞毒性T细胞 突变体 癌症 顺铂 分子生物学 药理学 内科学 细胞培养 化疗 生物 基因 体外 遗传学
作者
Naoise C Synnott,Aisling Murray,Norma O’Donovan,John Crown,Michael J. Duffy
出处
期刊:Journal of Clinical Oncology [American Society of Clinical Oncology]
卷期号:34 (15_suppl): 1082-1082
标识
DOI:10.1200/jco.2016.34.15_suppl.1082
摘要

1082 Background: Despite intensive efforts, a validated targeted therapy for triple-negative breast cancer (TNBC) remains elusive. One of the most frequent genetic alterations identified in TNBC is mutation in the p53 gene, which is found in > 80% of samples. The aim of this study was therefore to investigate the potential value of the mutant p53 reactivating compound, APR-246 for the treatment of TNBC. Methods: Cell viability was determined using the MTT assay. p53 protein levels were determined using Western blot and ELISA while both p63 and p73 levels were measured by Western blotting. Results: Based on a panel of 23 breast cancer cell lines, significantly lower IC50 values were found in p53 mutant compared to p53 wild-type cells (p= 0.014). Furthermore, a significant inverse correlation was found between IC50 values and p53 protein levels (p= 0.0001, r= -0.76). We also related response with levels of the p53 family members, p63 and p73. A significant inverse correlation was found between p63 protein levels and IC50 values (p= 0.01, r= -0.55). In contrast, no correlation was seen between p73 protein level and IC50 values. In an attempt to enhance response, APR-246 was combined with different cytotoxic agents. Both docetaxel and carboplatin showed an additive effect in combination with APR-246. However, this additive effect was cell line-dependent, i.e., docetaxel plus APR-246 was additive in MDA-MB-453 cells (CI = 0.92) cells but not in MDA-MB-468 cells (CI = 1.7), while carboplatin plus APR-246 was additive in MDA-MB-468 cells (CI = 0.94) but not in MDA-MB-453 cells (CI = 1.2). Conclusions: Based on our finding, either the mutational status of the p53 gene or p53 protein levels may be used to predict response to APR-246. Clinical trials investigating this agent should incorporate either or both of these measurements as potential predictive biomarkers.

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