JCI：p53与三阴性乳腺癌的治疗

三阴性乳腺癌（TNBC）是指雌激素受体（ER）、孕激素受体（PR）和人表皮生长因子受体（HER2）均阴性的一种特殊类型乳腺癌。

治疗TNBC需要一种靶向治疗策略。TNBCs的TP53频繁的突变，导致了G1检验点的丢失。

之前的研究表明，由于细胞的p53缺陷，当应答DNA损伤时，Chk1被抑制。为了研究抑制Chk1是否能够增强DNA损伤药剂伊立替康对TNBC的细胞毒性，美国华盛顿大学医学院的Helen Piwnica-Worms等人使用了异种移植肿瘤模型。

实验中，TNBC患者的肿瘤标本被移植到免疫缺陷老鼠的乳房脂肪垫上，结果创建3个独立的人类三阴性乳腺癌老鼠移植瘤细胞系：一种WT(WU-BC3)，两种TP53突变(WU-BC4和WU-BC5)。

随后的实验利用这些细胞系应答伊立替康及另一种Chk1抑制剂（UCN-01或者AZD7762），实验中采用单独使用药物或者是联合作用。结果发现，在WU-BC4及WU-BC5,而不是WU-BC3，联合治疗引起了检验点旁路及细胞凋亡。

此外，联合治疗抑制了肿瘤的增长，延长了移植了WU-BC4细胞系的老鼠的成活时间，但是对WU-BC3细胞系没有明显改观。除此以外，敲除p53能够致使WU-BC3移植瘤对联合治疗敏感。

这些结果表明TNBCs在应答于结合DNA损伤及Chk1抑制的治疗过程中，p53是一个主要的决定因素。相关论文发表在3月26日The Journal of Clinical Investigation。（生物谷Deepblue编译）

doi: 10.1172/JCI58765
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Targeting Chk1 in p53-deficient triple-negative breast cancer is therapeutically beneficial in human-in-mouse tumor models

Cynthia X. Ma, Shirong Cai, Shunqiang Li, Christine E. Ryan, Zhanfang Guo, W. Timothy Schaiff, Li Lin, Jeremy Hoog, Reece J. Goiffon, Aleix Prat, Rebecca L. Aft, Matthew J. Ellis and Helen Piwnica-Worms.

Patients with triple-negative breast cancer (TNBC) — defined by lack of estrogen receptor and progesterone receptor expression as well as lack of human epidermal growth factor receptor 2 (HER2) amplification — have a poor prognosis.There is a need for targeted therapies to treat this condition. TNBCs frequently harbor mutations in TP53, resulting in loss of the G1 checkpoint and reliance on checkpoint kinase 1 (Chk1) to arrest cells in response to DNA damage.Previous studies have shown that inhibition of Chk1 in a p53-deficient background in response to DNA damage. We therefore tested whether inhibition of Chk1 could potentiate the cytotoxicity of the DNA damaging agent irinotecan in TNBC using xenotransplant tumor models.Tumor specimens from patients with TNBC were engrafted into humanized mammary fat pads of immunodeficient mice to create 3 independent human-in-mouse TNBC lines: 1 WT (WU-BC3) and 2 mutant for TP53 (WU-BC4 and WU-BC5).These lines were tested for their response to irinotecan and a Chk1 inhibitor (either UCN-01 or AZD7762), either as single agents or in combination. The combination therapy induced checkpoint bypass and apoptosis in WU-BC4 and WU-BC5, but not WU-BC3, tumors.Moreover, combination therapy inhibited tumor growth and prolonged survival of mice bearing the WU-BC4 line, but not the WU-BC3 line. In addition, knockdown of p53 sensitized WU-BC3 tumors to the combination therapy.These results demonstrate that p53 is a major determinant of how TNBCs respond to therapies that combine DNA damage with Chk1 inhibition.