Targeting the WASF3 Regulatory Complex in Pancreatic Cancer Using Stapled Peptides

Wiskott-Aldrich Syndrome Protein Family (WASF) members form a heteropentameric complex along with ABI1/2, NCKAP1, CYFIP1/2, and BRK1, termed the WASF Regulatory Complex (WRC), which regulates actin cytoskeletal remodeling. Upregulated WASF3 has been identified in pancreatic cancer and is associated with a poor prognosis, increased invasion, and metastasis. In this study, we sought to determine whether disruption of the WRC could suppress WASF3-mediated actin polymerization and subsequent cellular invasion and motility in pancreatic cancer cells. Here, we screened constrained peptides designed to disrupt the formation of the WRC at multiple protein-protein interfaces. The WASF3-derived constrained peptide WAHM1 was found to suppress cell motility and invasion in PANC-1 and BxPC-3 cells. Further, WAHM1 was found to permeate pancreatic cancer cell lines, bind to its protein targets in the WRC, and reduce WRC protein levels. WAHM1 may serve as a complementary strategy to downregulate WASF3-mediated migration and invasion in pancreatic cancer models.