早期研究结果显示，多腺苷二磷酸核糖聚合酶（PARP）抑制剂治疗BRCA缺陷乳腺癌很有希望，然而最终发生耐药。此外，PARP抑制剂对三阴性乳腺癌的益处仍然未知。最近的证据表明，在三阴性乳腺癌中表现出“癌干细胞”特征的细胞对常规治疗有耐药性，导致肿瘤转移并引起复发。乳腺癌干细胞对PARP抑制剂的敏感性亦未知。
2016年12月29日，美国癌症研究学会官方期刊《临床癌症研究》正式发表密歇根大学综合癌症中心、中山大学孙逸仙纪念医院、复旦大学（上海医学院）附属肿瘤医院、中国科学技术大学生命科学学院与医学中心的研究报告，发现DNA双链断裂同源重组修复基因蛋白（RAD51）可致三阴性乳腺癌干细胞对PARP抑制剂耐药。
该研究在BRCA1突变型、野生型三阴性乳腺癌细胞系和肿瘤异种移植物中，确定乳腺癌干细胞对PARP抑制剂的敏感性，还分析了RAD51在这些体外和体内模型中引起癌干细胞对PARP抑制剂耐药的作用。
结果发现，BRCA1突变型三阴性乳腺癌干细胞对PARP抑制剂耐药，这些细胞的RAD51蛋白水平和活性均升高。通过短发夹RNA（shRNA）致敏癌干细胞下调RAD51可抑制PARP并抑制肿瘤生长。BRCA1野生型细胞单用PARP抑制剂相对耐药，但是减少RAD51可使这些肿瘤中的癌干细胞和体细胞对PARP抑制剂治疗敏感。
因此，该研究表明在BRCA1突变型和BRCA1野生型三阴性乳腺癌中，癌干细胞对PARP抑制剂相对耐药。该耐药性由RAD51引起，表明靶向RAD51的策略可以增加PARP抑制剂的治疗效果。
Clin Cancer Res. 2016 Dec 29. [Epub ahead of print]
RAD51 Mediates Resistance of Cancer Stem Cells to PARP Inhibition in Triple-Negative Breast Cancer.
Liu Y, Burness ML, Martin-Trevino R, Guy J, Bai S, Harouaka R, Brooks MD, Shang L, Fox A, Luther TK, Davis A, Baker TL, Colacino J, Clouthier SG, Shao ZM, Wicha MS, Liu S.
University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan; Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China; School of Life Science and Medical Center, University of Science and Technology of China, Hefei, China.
INTRODUCTION: PARP inhibitors have shown promising results in early studies for treatment of breast cancer susceptibility gene (BRCA)-deficient breast cancers; however, resistance ultimately develops. Furthermore, the benefit of PARP inhibitors (PARPi) in triple-negative breast cancers (TNBC) remains unknown. Recent evidence indicates that in TNBCs, cells that display "cancer stem cell" properties are resistant to conventional treatments, mediate tumor metastasis, and contribute to recurrence. The sensitivity of breast cancer stem cells (CSC) to PARPi is unknown.
METHODS: We determined the sensitivity of breast CSCs to PARP inhibition in BRCA1-mutant and -wild-type TNBC cell lines and tumor xenografts. We also investigated the role of RAD51 in mediating CSC resistance to PARPi in these in vitro and in vivo models.
RESULTS: We demonstrated that the CSCs in BRCA1-mutant TNBCs were resistant to PARP inhibition, and that these cells had both elevated RAD51 protein levels and activity. Downregulation of RAD51 by shRNA sensitized CSCs to PARP inhibition and reduced tumor growth. BRCA1-wild-type cells were relatively resistant to PARP inhibition alone, but reduction of RAD51 sensitized both CSC and bulk cells in these tumors to PARPi treatment.
CONCLUSIONS: Our data suggest that in both BRCA1-mutant and BRCA1-wild-type TNBCs, CSCs are relatively resistant to PARP inhibition. This resistance is mediated by RAD51, suggesting that strategies aimed at targeting RAD51 may increase the therapeutic efficacy of PARPi.
PMID: 28034904
DOI: 10.1158/1078-0432.CCR-15-1348
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