Gastric cancer (GC) is one of the most common malignancies worldwide. The prognosis of GC is unsatisfied owning to widespread metastasis. P21-activated kinase 1 (PAK1), a member of serine/threonine kinases, is associated with the progression of multiple types of human cancers. Here, we demonstrated that CDK4/6 inhibitor reduced GC cell viability and decreased PAK1 expression. Consistently, PAK1 ablation increased GC cell sensitivity exposed to CDK4/6 inhibitor and promoted DNA damage. We also revealed PAK1 depletion notably affected PDK1-AKT pathway, and PDK1 overexpression totally abrogated the effect of PAK1 deletion on DNA damage in GC cells. Additionally, PDK1 overexpression also rescued the increased GC cell sensitivity towards CDK4/6 inhibitor and the cell cycle arrest caused by PAK1 depletion. Our findings, therefore, suggested that PAK1 silencing increased sensitivity to CDK4/6 inhibition in gastric cancer cells via PDK1–AKT pathway. We, therefore, thought PAK1 as a promising therapeutic target for the treatment of CDK4/6 inhibitor-resistant gastric cancer.

中文翻译：

---

PAK1 沉默是合成致死的，通过调节 PDK1 表达抑制胃癌细胞中的 CDK4/6。

胃癌（GC）是全球最常见的恶性肿瘤之一。由于广泛转移，GC的预后不理想。P21 活化激酶 1 (PAK1) 是丝氨酸/苏氨酸激酶的成员，与多种人类癌症的进展有关。在这里，我们证明了 CDK4/6 抑制剂降低了 GC 细胞活力并降低了 PAK1 的表达。一致地，PAK1 消融增加了暴露于 CDK4/6 抑制剂的 GC 细胞敏感性并促进了 DNA 损伤。我们还发现 PAK1 缺失显着影响了 PDK1-AKT 通路，并且 PDK1 过表达完全消除了 PAK1 缺失对 GC 细胞 DNA 损伤的影响。此外，PDK1 过表达还挽救了 GC 细胞对 CDK4/6 抑制剂的敏感性增加和 PAK1 耗竭引起的细胞周期停滞。因此，我们的发现 表明 PAK1 沉默通过 PDK1-AKT 途径增加了对胃癌细胞中 CDK4/6 抑制的敏感性。因此，我们认为 PAK1 是治疗 CDK4/6 抑制剂耐药性胃癌的有希望的治疗靶点。