MerTK inhibition by UNC569 triggers DNA damage and JNK/p38 MAPK cascade-driven apoptosis in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with increasing mortality rates and remains a major clinical challenge due to its aggressive progression and limited therapeutic options. Therefore, the identification of early biomarkers and the development of effective targeted therapies are critically needed. MerTK, a receptor tyrosine kinase aberrantly expressed in various cancers, can be selectively inhibited by UNC569, a small-molecule antagonist with demonstrated efficacy in hematologic malignancies. This study shows that UNC569 potently suppresses PDAC cell proliferation and clonogenic growth, inhibits migration and invasion by attenuating epithelial-mesenchymal transition (EMT), and enhances the sensitivity of PDAC cells to Gemcitabine (GEM) while promoting apoptosis. Mechanistically, UNC569 induces DNA damage-mediated G2/M phase arrest and activates JNK/p38 mitogen-activated protein kinase (MAPK)-dependent apoptotic signaling. Collectively, these results establish MerTK as a promising therapeutic target in PDAC and highlight the translational potential of UNC569 as a dual-pathway inhibitor for PDAC treatment.