Inhibition of c-MET reverses radiation-induced malignant potential in pancreatic cancer

As a treatment option for PDAC, radiation therapy induces good local control. However, radiation also reportedly enhances the malignant potential (e.g., invasion and migration ability) in various cancers, thus increasing the risk of distant metastasis. It remains unclear how radiation induces malignant potential, and how such enhanced malignant potential can be suppressed. In the current study, we evaluated the sequential change of c-Met expression in pancreatic cancer cells following irradiation. We found that irradiation transiently induced c-Met expression in vitro. In an in vivo subcutaneous tumor mouse model, irradiation also enhanced downstream phosphorylated Met (p-Met). Furthermore, this enhancement of p-Met protein expression was suppressed by oral administration of the c-Met inhibitor INC280. Irradiated pancreatic cancer cells with enhanced c-Met expression exhibited higher malignant potential, including invasion and migration ability, compared with cells showing low c-Met expression. Pancreatic cancer cells that overexpressed c-met also showed enhanced malignant potential, which was reversed by c-Met inhibition. Additionally, c-Met inhibitor suppressed the metastatic potential in a liver metastasis mouse model using c-met-overexpressing cells. Overall, our present results revealed that irradiation could induce c-met expression in pancreatic cancer cells, leading to enhanced malignant potential (e.g., invasion and migration ability) and thus promoting distant metastasis. Moreover, a c-Met inhibitor could reverse this enhanced malignant potential.