Rac和Cdc42抑制剂作为胰腺癌治疗药物的潜力

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest forms of cancer, with a distinct extracellular matrix and immunosuppressive tumor microenvironment. Existing chemotherapies are hampered by toxicity and demonstrate poor clinical response. Therapies targeting the KRAS G12D mutation, prevalent in pancreatic cancer, have yet to receive FDA approval. Therefore, there is a critical need for novel targeted therapies for PDAC. These therapies should simultaneously target metastatic cancer cells and immunosuppressive cells such as tumor-associated macrophages (TAMS), since they promote pancreatic cancer progression. Ras-activated related GTPases Rac and Cdc42 are ideal targets for pancreatic cancer therapy because they regulate migration, invasion, polarity, viability, and survival in cancer cells and immune cells. Therefore, we developed Rac and Cdc42 inhibitors for metastatic diseases such as PDAC to target cancer and its immunosuppressive environment. The hypothesis tested in this study is that Rac/Cdc42 inhibitors will simultaneously target the migration and activity of cancer cells and macrophage-like cells in the TME. We assessed the potential of the dual Rac and Cdc42 inhibitors MBQ-167 and MBQ-168, which block guanine nucleotide association with Rac and Cdc42. The effects of vehicle, MBQ-167 or MBQ-168 were tested in human and mouse PDAC cells or macrophages by performing pulldown assays for Rac and Cdc42 activation, MTT assays for cell viability, wound-healing assays for cell migration, phagocytosis, as well as co-culture assays with PDAC cells and macrophages. Results demonstrated that Rac and Cdc42 inhibitors significantly reduced active Rac and Cdc42 in pancreatic and macrophage cells. Both MBQ-167 and MBQ-168 reduced pancreatic cancer cell viability, without affecting macrophage viability, and inhibited cell morphology and migration. In co-culture using Transwells, MBQ-167 and MBQ-168 decreased pancreatic cancer cell migration from the top wells, with macrophages in the bottom wells, and reduced inflammatory mediators such as IL-6, CHI3L1 and S100A8 and S100A9 levels in conditioned media. A preliminary study was also conducted in C57BL6 mice bearing orthotopic KPC (KRas G12D, p53 null, Cre) tumors to test the effect of vehicle or 10mg MBQ-167 administered by IP 5X a week for 21 days. MBQ-167 treatment decreased tumor growth and increased survival compared to vehicle treatments. In conclusion, MBQ-167 and MBQ-168 pose as potential therapeutics for PDAC due to their ability to target both pancreatic and macrophage-like cells.