Overcoming resistance of stroma-rich pancreatic cancer with focal adhesion kinase inhibitor combined with G47A and immune checkpoint inhibitors

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease known for its dense tumor stroma. Focal adhesion kinase inhibitor (FAKi), a non-receptor type tyrosine kinase inhibitor, reduces the tumor stroma. G47A, a third-generation oncolytic herpes simplex virus type 1, destroys tumor cells selectively and induces antitumor immune responses. This study evaluates the efficacy of FAKi and G47A in PDAC models in combination with or without immune checkpoint inhibitors. G47A was effective in human PDAC cell lines in vitro and in subcutaneous as well as orthotopic tumor models. Transgenic mouse-derived #146 cells were used to generate subcutaneous PDAC tumors with rich stroma in immunocompetent mice. In this #146 tumor model, the efficacy of FAKi was synergistically augmented when combined with G47A, which reflected not only a decreased stromal content but also a significant shifting of the tumor microenvironment toward immune stimulation. In transgenic autochthonous PKF mice, a rare model that develops stroma-rich PDAC with a 100% penetrance and resembles human PDAC in various aspects, the prolongation of survival compared with FAKi alone was achieved only when FAKi was combined with G47A and immune checkpoint inhibitors. treatment resistance of stroma-rich PDAC.