mTOR信号通路调控在三阴乳腺癌PARP抑制剂耐药中的作用及机制研究

Breast cancer patients with BRCA1/2 mutations and those with triple-negative breast cancer has no effective treatment and has poor prognosis.PARP inhibitors constitute a new class of drugs now being investigated as treatment for this differential group of patients.Despite success in laboratory research on PARP inhibitors, recent clinical trials have shown rather disappointing results. Our past experiment inferred that rapamycin may cause PARP inhibitor sensitizing molecular status.In order to identify the mechanisms of PARP inhibitor resistance and develop strategies to combat resistance in breast cancer patients,we hypothese that aberrant mTOR signaling in breast cancer confers resistance to PARP inhibitors by regulating DNA repair processes. We will take integrated approaches combining in vitro and in vivo assays to test our hypothesis both at the mechanistic level and at the preclinical level.The specific work to test this hypothesis are,1)Define the functional and mechanistic basis for regulating DNA repair by aberrant mTOR signaling,including identify the effects of inhibition of mTOR signaling on the recruitment of DNA damage detecting, signaling, and repairing proteins to DSBs,and identify mTOR binding partners and determine how the interaction affects HR repair. 2)Establish the impact of genetic alterations in mTOR signaling on PARP inhibitor resistance and determine whether the alterations can be used as predictive markers for resistance.3)Measure the therapeutic effects of mTOR/PARP inhibitor combinations on breast cancer both in vitro and in vivo.We expect the test of our hypothesis to provide a mechanistic basis for evaluating mTOR/PARP inhibitor combination therapy for breast cancer ,and help to improve the therapeutic effect for triple-negative breast cancer.

三阴乳腺癌(TNBC)因恶性程度高，易复发转移，疗效和预后极差，是当前乳腺癌治疗领域的难点。TNBC常伴BRCA1/2基因突变，两者存在紧密联系。基础研究提示PARP抑制剂针对TNBC或BRCA突变型乳腺癌有良好应用前景，但临床研究却显示疗效欠佳，因此探寻PARP抑制剂的耐药机制成为TNBC或BRCA突变型乳腺癌研究领域的关键。课题组前期研究结果揭示mTOR信号通路异常调控可能通过调节同源重组途径(HR)介导的DNA损伤修复，与PARP抑制剂耐药密切相关。本研究拟进一步探索mTOR信号通路异常调控对DNA损伤修复进程的影响及具体分子机制，研究mTOR信号通路异常调控对PARP抑制剂耐药的预测作用，通过细胞和移植瘤模型验证mTOR抑制剂和PARP抑制剂联合作用的体内外抗瘤效应。本研究旨在阐明TNBC或BRCA突变型乳腺癌PARP抑制剂耐药分子机制，并为克服PARP抑制剂耐药提供新的治疗靶点。

三阴乳腺癌(TNBC)因恶性程度高，易复发转移，疗效和预后极差，是当前乳腺癌治疗领域的难点。TNBC常伴BRCA1/2基因突变，两者存在紧密联系。基础研究提示PARP抑制剂针对TNBC或BRCA突变型乳腺癌有良好应用前景，但临床研究却显示疗效欠佳。本次实验我们发现mTOR抑制剂对三阴性乳腺癌细胞中同源重组修复具有抑制作用，并从细胞水平和体内水平证实PARP抑制剂联合mTOR抑制剂对乳腺癌具有抗瘤作用。该结果为临床上使用PARP抑制剂联合mTOR抑制剂治疗三阴性乳腺癌提供了理论依据。此外，我们开发出一种新型高通量成像分析技术，可筛选出同源重组修复抑制剂。并首次发现β-thujaplicin可作为同源重组修复抑制剂，通过抑制同源重组修复过程的关键蛋白Rad51来抑制同源重组修复。此外，β-thujaplicin可增加肿瘤细胞对放疗及PARP抑制剂的敏感性。该结果为临床上增加肿瘤患者对放疗及PARP抑制剂的敏感性提供了一种新的可能性。