Many patients with late-stage pancreatic cancer develop resistance to various treatments including first-line chemotherapy, highlighting a need to identify and understand the mechanisms of resistance. To provide insights, researchers led by Yohei Saito, Ph.D., Yi Xiao, Ph.D., and Dihua Yu, M.D., Ph.D., examined single-cell transcriptomic data from models of pancreatic cancer and clinical pathological information from patients with pancreatic cancer.
They discovered a novel signaling circuit – Yap1 in cancer cells and Cox2 in fibroblasts of tumor microenvironment – that is activated during chemotherapy and helps these cancer cells survive. Co-targeting Yap1 in cancer cells and Cox2 in fibroblasts effectively overcame chemotherapy resistance and significantly extended survival in preclinical models. Interestingly, clinical analyses revealed that patients with pancreatic cancer who received statins, which inhibit Yap1, and aspirin, which targets Cox2, had prolonged survival during chemotherapy. These findings further highlight the therapeutic potential of co-targeting this signaling circuit to overcome resistance and improve patient outcomes.