三陰性乳腺癌（TNBC）是指雌激素受體（ER）,、孕激素受體（PR）和人表皮生長(zhǎng)因子受體（HER2）均陰性的一種特殊類型乳腺癌,。
治療TNBC需要一種靶向治療策略,。TNBCs的TP53頻繁的突變，導(dǎo)致了G1檢驗(yàn)點(diǎn)的丟失,。
之前的研究表明，由于細(xì)胞的p53缺陷,，當(dāng)應(yīng)答DNA損傷時(shí),，Chk1被抑制。為了研究抑制Chk1是否能夠增強(qiáng)DNA損傷藥劑伊立替康對(duì)TNBC的細(xì)胞毒性,，美國(guó)華盛頓大學(xué)醫(yī)學(xué)院的Helen Piwnica-Worms等人使用了異種移植腫瘤模型,。
實(shí)驗(yàn)中，TNBC患者的腫瘤標(biāo)本被移植到免疫缺陷老鼠的乳房脂肪墊上,，結(jié)果創(chuàng)建3個(gè)獨(dú)立的人類三陰性乳腺癌老鼠移植瘤細(xì)胞系：一種WT(WU-BC3),，兩種TP53突變(WU-BC4和WU-BC5)。
隨后的實(shí)驗(yàn)利用這些細(xì)胞系應(yīng)答伊立替康及另一種Chk1抑制劑（UCN-01或者AZD7762）,，實(shí)驗(yàn)中采用單獨(dú)使用藥物或者是聯(lián)合作用,。結(jié)果發(fā)現(xiàn)，在WU-BC4及WU-BC5,而不是WU-BC3,，聯(lián)合治療引起了檢驗(yàn)點(diǎn)旁路及細(xì)胞凋亡。
此外,，聯(lián)合治療抑制了腫瘤的增長(zhǎng),，延長(zhǎng)了移植了WU-BC4細(xì)胞系的老鼠的成活時(shí)間，但是對(duì)WU-BC3細(xì)胞系沒有明顯改觀,。除此以外,，敲除p53能夠致使WU-BC3移植瘤對(duì)聯(lián)合治療敏感。
這些結(jié)果表明TNBCs在應(yīng)答于結(jié)合DNA損傷及Chk1抑制的治療過程中,，p53是一個(gè)主要的決定因素,。相關(guān)論文發(fā)表在3月26日The Journal of Clinical Investigation。（生物谷Deepblue編譯）
doi: 10.1172/JCI58765
PMC:
PMID:
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.
