弥漫型胃癌（DGC）是胃癌的一种亚型，具有侵袭性和预后不良。寻找DGC敏感药物具有重要意义。本研究共分析了20个患者来源的类器官（PDO），以筛选小分子激酶抑制剂对胃癌的治疗效果，特别是肠型胃癌（IGC）和DGC的治疗差异。 IGC 对多种激酶抑制剂敏感，而 DGC 对大多数激酶抑制剂具有抗性。研究发现，DGCs经极光激酶抑制剂（AURKi）Barasertib-HQPA和Danusertib治疗后表现出药物诱导的衰老表型。癌细胞的细胞直径随着衰老相关β-半乳糖苷酶（SA-β-GAL）染色的增强而增加，并出现多核巨细胞的特征性外观。衰老癌细胞分泌大量趋化因子MCP-1/CCL2，在DGC（DPDOs）-巨噬细胞共培养系统的PDOs中募集并诱导巨噬细胞发生M2型极化。局部MCP-1/CCL2的上调可以与巨噬细胞上表达的MCP-1/CCL2受体(CCR2)相互作用，抑制其对癌细胞的先天免疫。总体而言，DGC 对 AURKi 的特殊反应建议临床医生在 AURKi 治疗 DGC 后应选择序贯治疗，清除衰老细胞。版权所有 © 2024。由 Elsevier B.V 出版。

Diffuse-type gastric cancer (DGC) is a subtype of gastric cancer with aggressiveness and poor prognosis. It is of great significance to find sensitive drugs for DGC. In the current study, a total of 20 patient-derived organoids (PDOs) were analyzed for screening the therapeutic efficacy of small molecule kinases inhibitors on gastric cancers, especially the therapeutic difference between intestinal-type gastric cancer (IGCs) and DGCs. The IGCs are sensitive to multiple kinases inhibitors, while DGCs are resistant to most of these kinases inhibitors. It was found that DGCs showed drug-induced senescent phenotype after treatment by aurora kinases inhibitors (AURKi) Barasertib-HQPA and Danusertib. The cell diameter of cancer cells are increased with stronger staining of senescence-associated β-galactosidase (SA-β-GAL), and characteristic appearance of multinucleated giant cells. The senescent cancer cells secrete large amounts of chemokine MCP-1/CCL2, which recruit and induce macrophage to M2-type polarization in PDOs of DGC (DPDOs)-macrophage co-culture system. The up-regulation of local MCP-1/CCL2 can interact with MCP-1/CCL2 receptor (CCR2) expressed on macrophages and suppress their innate immunity to cancer cells. Overall, the special response of DGC to AURKi suggests that clinicians should select a sequential therapy with senescent cell clearance after AURKi treatment for DGC.Copyright © 2024. Published by Elsevier B.V.