UCD School of Medicine, University College Dublin, Dublin 4, Ireland.
Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
Cancer Lett. 2018 Feb 1;414:99-106. doi: 10.1016/j.canlet.2017.09.053. Epub 2017 Oct 22.
The identification of a targeted therapy for patients with triple-negative breast cancer (TNBC) is one of the most urgent needs in breast cancer therapeutics. The p53 gene is mutated in approximately 80% of patients with TNBC, and is a potential therapeutic target for patients with this form of breast cancer. The 2-sulfonylpyrimidine compound, PK11007, preferentially decreases viability in p53-compromised cancer cell lines. We investigated PK11007 as a potential new treatment for TNBC. IC values for inhibition of proliferation in a panel of 17 breast cell lines by PK11007 ranged from 2.3 to 42.2 μM. There were significantly lower IC values for TNBC than for non-TNBC cell lines (p = 0.03) and for p53-mutated cell lines compared with p53 WT cells (p = 0.003). Response to PK11007 however, was independent of the estrogen receptor (ER) or HER2 status of the cell lines. In addition to inhibiting cell proliferation, PK11007 induced apoptosis in p53 mutant cell lines. Using RNAseq and gene ontology analysis, we found that PK11007 altered the expression of genes enriched in pathways involved in regulated cell death, regulation of apoptosis, signal transduction, protein refolding and locomotion. The observations that PK11007 inhibited cell proliferation, induced apoptosis and altered genes involved in cell death are all consistent with the ability of PK11007 to reactivate mutant p53. Based on our data, we conclude that targeting mutant p53 with PK11007 is a potential approach for treating p53-mutated breast cancer, including the subgroup with TN disease.
鉴定针对三阴性乳腺癌 (TNBC) 患者的靶向治疗方法是乳腺癌治疗中最迫切的需求之一。大约 80%的 TNBC 患者存在 p53 基因突变，这使其成为此类乳腺癌患者的潜在治疗靶点。2-磺酰基嘧啶化合物 PK11007 可优先降低 p53 缺陷型癌细胞系的活力。我们研究了 PK11007 作为治疗 TNBC 的一种潜在新方法。PK11007 抑制 17 种乳腺癌细胞系增殖的 IC 值范围为 2.3 至 42.2μM。TNBC 的 IC 值明显低于非 TNBC 细胞系（p=0.03）和 p53 突变细胞系与 p53 WT 细胞相比（p=0.003）。然而，对 PK11007 的反应与细胞系的雌激素受体 (ER) 或 HER2 状态无关。除了抑制细胞增殖外，PK11007 还诱导 p53 突变细胞系中的细胞凋亡。通过 RNAseq 和基因本体分析，我们发现 PK11007 改变了参与受调控细胞死亡、细胞凋亡调节、信号转导、蛋白质重折叠和运动的途径中富集的基因的表达。PK11007 抑制细胞增殖、诱导细胞凋亡和改变参与细胞死亡的基因的观察结果都与 PK11007 重新激活突变型 p53 的能力一致。基于我们的数据，我们得出结论，用 PK11007 靶向突变型 p53 是治疗包括 TN 疾病在内的 p53 突变型乳腺癌的潜在方法。
