Drug-induced senescence by aurora kinase inhibitors attenuates innate immune response of macrophages on gastric cancer organoids.

ABSTRACT

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 ß-galactosidase (SA-ß-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.