WSB1调控非同源末端连接修复在克服PARP抑制剂天然耐药中的机制研究

The PARP inhibitor is the first antitumor drug that has successfully used the "synthetic lethal" concept. It is currently only suitable for tumor patients with BRCA mutations. How to overcome the intrinsic resistance of PARP inhibitors in BRCA wild type tumors and to expand their application range have been attracted lots of attention in this field for a long time. In our preliminary study, we interestingly found WSB1 positively determined the antitumor activity of PARP inhibitors on cancer cells regarding less the BRCA1/2 status. The mechanistic study suggests that the WSB1-mediated the ubiquitination of XLF selectively activates NHEJ repair signal instead of HR repair, which subsequently cause the robust genome instability after treating with PARP inhibitors in BRCA1/2 wild type cancer cells. Basing on these findings, we are planning to further confirm the role of WSB1 in the sensitivity of PARP inhibitors on BRCA1/2 wild type cancer cells and also intensively explore the molecular mechanism behind this effect especially focusing on the XLF-NHEJ repair signaling. The novelty and significance of this study lie in several aspects: (1) This is the first time WSB1 is found to regulate PARP inhibitors effect. This provides the exciting possibility that WSB1 could be served as the biomarker for predicting the effect of PARP inhibitors even in BRCA1/2 wild type cancer patient. (2) The selective activation of NHEJ/HR repair signaling determined by WSB1 expands the known regulation network of DNA double strains break repair, which has been appreciated for decades. (3) The finding opens new exciting opportunities to develop new cancer therapy basing on the “BER/NHEJ” synthetic lethality.

PARP抑制剂是第一种成功利用“合成致死”概念研发上市的抗肿瘤药物，目前临床仅适用于BRCA突变的肿瘤病人。如何克服PARP抑制剂在BRCA野生型肿瘤中的天然耐药，拓展其应用范围一直是该领域研究的重点方向。我们在前期研究中发现WSB1正性调控了BRCA野生型肿瘤细胞对PARP抑制剂的敏感性，且其潜在的作用机制是通过泛素化修饰XLF蛋白使细胞偏好性启动NHEJ修复DNA双链损伤，进而导致致死性突变形成。本项目将在此基础上，进一步研究WSB1正性调控NHEJ修复途径的方式及其在PARP抑制剂敏感性中的分子机制。本项目的研究不仅有望克服PARP抑制剂天然耐药限制，为扩大其抗肿瘤应用范围提供实验依据和潜在的分子标记物；而且可在分子层面揭示WSB1在DNA双链损伤修复途径中的全新调控方式，并有望揭示以“BER／NHEJ”为基础的“合成致死”新模式，具有重要的理论价值和潜在的临床应用前景。

PARP抑制剂是第一种成功利用“合成致死”概念研发上市的抗肿瘤药物，目前临床仅适用于BRCA突变的肿瘤病人。如何克服PARP抑制剂在BRCA野生型肿瘤中的天然耐药，拓展其应用范围一直是该领域研究的重点方向。本项目研究发现WSB1正性调控了BRCA野生型肿瘤细胞对PARP抑制剂的敏感性并阐明了其作用模式，即WSB1作为E3泛素连接酶，通过调控其底物蛋白MOR4L1的泛素化修饰水平抑制同源重组（HR）修复，同时驱使细胞被迫启动非同源末端连接（NHEJ）修复，介导了DNA损伤修复偏好性改变，大大增加了细胞内基因组不稳定性。本项目的顺利开展不仅阐明了WSB1蛋白与PARP抑制剂敏感性之间的关系，为克服PARP 抑制剂天然耐药，扩大PARP 抑制剂适应症提供了实验依据和潜在的分子标记物；而且在分子层面揭示了WSB1 在DNA 双链损伤修复途径选择中的调控方式，并有望展现以“BER（剪辑切除修复）／NHEJ”为基础的一种“合成致死”新方式，具有重要的理论研究价值和潜在的临床应用前景。