Chemoresistance remains the primary challenge of clinical treatment of gastric cancer (GC), making the biomarkers of chemoresistance crucial for treatment decision. Our previous study has reported that p21-actived kinase 6 (PAK6) is a prognostic factor for selecting which patients with GC are resistant to 5-fluorouracil/oxaliplatin chemotherapy. However, the mechanistic role of PAK6 in chemosensitivity remains unknown. The present study identified PAK6 as an important modulator of the DNA damage response (DDR) and chemosensitivity in GC. Analysis of specimens from patients revealed significant associations between the expression of PAK6 and poorer stages, deeper invasion, more lymph node metastases, higher recurrence rates, and resistance to oxaliplatin. Cells exhibited chemosensitivity to oxaliplatin after knockdown of PAK6, but showed more resistant to oxaliplatin when overexpressing PAK6. Functionally, PAK6 mediates cancer chemoresistance by enhancing homologous recombination (HR) to facilitate the DNA double-strand break repair. Mechanistically, PAK6 moves into nucleus to promote the activation of ATR, thereby further activating downstream repair protein CHK1 and recruiting RAD51 from cytoplasm to the DNA damaged site to repair the broken DNA in GC. Activation of ATR is the necessary step for PAK6 mediated HR repair to protect GC cells from oxaliplatin-induced apoptosis, and ATR inhibitor (AZD6738) could block the PAK6-mediated HR repair, thereby reversing the resistance to oxaliplatin and even promoting the sensitivity to oxaliplatin regardless of high expression of PAK6. In conclusion, these findings indicate a novel regulatory mechanism of PAK6 in modulating the DDR and chemoresistance in GC and provide a reversal suggestion in clinical decision.

化疗耐药仍然是胃癌 (GC) 临床治疗的主要挑战，这使得化疗耐药的生物标志物对治疗决策至关重要。我们之前的研究报告称，p21 活化激酶 6 (PAK6) 是选择哪些 GC 患者对 5-氟尿嘧啶/奥沙利铂化疗耐药的预后因素。然而，PAK6 在化学敏感性中的机制作用仍然未知。本研究将 PAK6 鉴定为 GC 中 DNA 损伤反应 (DDR) 和化学敏感性的重要调节剂。对患者标本的分析表明，PAK6 的表达与较差的分期、较深的浸润、较多的淋巴结转移、较高的复发率和对奥沙利铂的耐药性之间存在显着关联。PAK6 敲低后细胞对奥沙利铂表现出化学敏感性，但过表达 PAK6 时对奥沙利铂表现出更强的耐药性。在功能上，PAK6 通过增强同源重组 (HR) 促进 DNA 双链断裂修复来介导癌症化学耐药性。从机制上讲，PAK6 进入细胞核促进 ATR 的激活，从而进一步激活下游修复蛋白 CHK1 并将 RAD51 从细胞质募集到 DNA 损伤位点以修复 GC 中的断裂 DNA。ATR 的激活是 PAK6 介导的 HR 修复保护 GC 细胞免受奥沙利铂诱导的细胞凋亡的必要步骤，ATR 抑制剂 (AZD6738) 可以阻断 PAK6 介导的 HR 修复，从而逆转对奥沙利铂的耐药性，甚至提高对奥沙利铂的敏感性无论 PAK6 的高表达如何。综上所述，