转录因子FOXM1调控PARP抑制剂olaparib耐药性的分子机制研究

以olaparib为代表的PARP抑制剂适应症已拓宽到三阴性乳腺癌、胰腺癌等多种存在DNA损伤应答突变的难治癌症。然而，PARP抑制剂耐药性问题却限制了该类药物的应用。DNA修复途径的恢复是肿瘤细胞对PARP抑制剂产生耐药性的主要原因。目前，多种激酶被证明可促进损伤DNA的修复，是逆转PARP抑制剂耐药性的潜在靶点。与激酶相比，转录因子对DNA修复途径的调节更加直接和有效。申请人前期研究发现olaparib耐药型三阴性乳腺癌细胞内存在DNA修复相关转录因子FOXM1的过度表达，抑制FOXM1的表达和功能可增加耐药细胞对olaparib的敏感性。这表明，FOXM1是逆转PARP抑制剂耐药性的潜在靶点。因此，本项目将以三阴性乳腺癌为研究对象，从DNA损伤修复的角度，揭示转录因子FOXM1调节olaparib耐药性的分子机制。期望本项目的实施能够为解决PARP抑制剂耐药性问题提供思路和理论依据。

The clinical indications of olaparib and other PARP inhibitors have expanded to triple negative breast cancer, pancreatic cancer and other cancers with DNA damage response mutation. However, the indications of PARP inhibitors have been limited by their drug resistance problems. The recovery of DNA repair pathway is the major reason for the resistance of tumor cells to PARP inhibitors. Currently, multiple kinases have been regarded as the potential targets for reversing the resistance of tumor cells to PARP inhibitor through promotion the repair of damaged DNA. Compared with kinases, the regulation of transcription factors in DNA repair pathways is more direct and effective. Our previous study has found that transcription factor FOXM1 was overexpressed in olaparib resistant cells. Impairing the expression and function of FOXM1 increased the sensitivity of resistant cells to olaparib. This suggests that FOXM1 is a potential target for reversing the resistance of tumor cells to PARP inhibitors. Therefore, this project will take triple negative breast cancer as research object to investigate the molecular mechanism of transcription factor FOXM1 regulating the resistance of triple negative breast cancer cells to olaparib from the perspective of DNA damage repair. The implementation of this project will provide idea and theoretical basis for resolving the problem of drug resistance of tumor cells to PARP1 inhibitor.