Cancer Letters

Diffuse-type gastric cancer (DGC) is a subtype of gastric cancer with aggressiveness andpoor 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 ongastric cancers, especially the therapeutic difference betweenintestinal-type gastric cancer (IGCs) and DGCs. The IGCs are sensitive to multiple kinases inhibitors, while DGCs are resistantto 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 -galactosidase (SA- -GAL), and characteristic appearance of multinucleated giant cells. The senescent cancer cells secrete large amounts of chemokine MCP-1/CCL2, which recruitand inducemacrophage to M2-type polarizationin PDOs of DGC (DPDOs)-macrophage co-culturesystem. The up-regulation of local MCP-1/CCL2 can interact with MCP-1/CCL2 receptor (CCR2)expressed on macrophages and suppress theirinnate immunity tocancer cells.Overall, the special response of DGC to AURKisuggests that clinicians should select a sequential therapy withsenescent cell clearanceafter AURKi treatment for DGC.