PBK通过磷酸化TRIM37促进卵巢癌对PARP抑制剂耐药的机制研究

Ovarian carcinoma is prone to recurrence and has high mortality, which is a serious threat to women's health. PARP inhibitors open the door to precise treatment of ovarian carcinoma. However, the mechanism of PARP inhibitor resistance is unclear. PBK (PDZ Binding Kinase) could promote PARP inhibitor resistance in BRCA1-deficient ovarian cancer cells. However, the specific mechanism has not been elucidated. Preliminary experimental results showed that PBK interacted with TRIM37, increased phosphorylation level of TRIM37 and promoted its nuclear translocation. Given that phosphorylated TRIM37 could activate NF-κB pathway through nuclear translocation, we also found that PBK activated NF-κB pathway. However, knockdown of TRIM37 or inhibition of NF-κB pathway could reverse PBK-induced drug resistance. Therefore, we hypothesize that PBK activates NF-κB pathway through phosphorylating TRIM37, thereby promoting PARP inhibitor resistance in ovarian carcinoma. In this research, we will verify this hypothesis from cell, animal model and clinical samples three levels. This research will help to elucidate the molecular mechanism of PARP inhibitor resistance, and provide new molecular target and strategy for overcoming PARP inhibitor resistance in ovarian carcinoma.

卵巢癌易复发、病死率高，严重威胁女性健康。PARP抑制剂开启了卵巢癌精准治疗的大门，但是PARP抑制剂耐药机制尚不明确。PDZ结合激酶（PBK）促进BRCA1缺失卵巢癌细胞对PARP抑制剂耐药，但PBK作用机制不清楚。预实验发现PBK可与TRIM37相互作用，并提高TRIM37磷酸化水平，促进其入核。鉴于磷酸化的TRIM37入核后可以激活NF-κB通路，结合预实验结果——PBK能够活化NF-κB通路，敲低TRIM37或阻断NF-κB通路都可以逆转PBK耐药作用。因此提出科学假设：PBK通过磷酸化TRIM37激活NF-κB通路，进而促进卵巢癌对PARP抑制剂耐药。本研究拟从细胞、动物模型以及临床样本三个层次证明该假设。本研究将有助于阐明卵巢癌对PARP抑制剂耐药的分子机制，为临床克服PARP抑制剂耐药提供新的靶点和策略。

卵巢癌是世界范围内致死率最高的妇科恶性肿瘤。传统的基于铂和紫杉醇的化疗方案疗效有限，70%的患者将在两年内复发。近年来，以奥拉帕尼为代表的PARP抑制剂(PARPi)已被批准用于一线化疗缓解后的晚期卵巢癌维持治疗。尽管PARPi维持治疗显著延长了卵巢癌患者的无进展生存期(PFS)，但越来越多的女性对PARPi产生原发性或获得性耐药。因此，阐明PARPi耐药机制，构建后续联合治疗策略具有重大临床价值。PDZ结合激酶(PBK)是被广泛报道的致癌蛋白，在多种恶性肿瘤的增殖、进展和转移中发挥重要作用。与正常组织相比，PBK在各种癌症中高度表达，因此PBK在恶性肿瘤的诊断、预后预测以及靶向治疗中具有广阔的应用前景。此外，PBK在多种恶性肿瘤的化疗和放疗耐药进程中发挥关键作用。然而，PBK在卵巢癌PARPi耐药中的作用尚不清楚。在本课题的研究中，我们研究发现过表达PBK导致卵巢癌细胞对奥拉帕尼耐药。敲低PBK增加耐药的卵巢癌细胞对奥拉帕尼敏感性。PBK小分子抑制剂OTS514有效增强奥拉帕尼治疗效果。进一步研究发现，PBK直接与TRIM37相互作用，促进其磷酸化和核转位，继而激活NFκB通路。此外，在细胞水平以及裸鼠模型中，PBK通过调控NFκB/TRIM37轴从而增加卵巢癌对奥拉帕尼的耐药性。综上所述，PBK通过激活TRIM37介导的NFκB通路促进卵巢癌对PARP抑制剂耐药，PBK有望成为卵巢癌靶向治疗新靶点，靶向抑制PBK为改善卵巢癌患者PARP抑制剂治疗效果提供新的治疗方法。