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

作者：Meng Guo, Junwan Lu, Yue Sun, Lan Wang, Wen Li, Peizhen Wang, Yao Deng, Zhijie Tan, Hanbin Chen, Yang Hu, Bin Lu, Rongrong Wang · 发表于：Acta Biochimica et Biophysica Sinica · 年份：2026 · DOI：10.3724/abbs.2026048 · 被引用次数：1 · 研究领域：Phagocytosis and Immune Regulation、Hippo pathway signaling and YAP/TAZ、FOXO transcription factor regulation

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, and enhances the sensitivity of PDAC cells to Gemcitabine while promoting apoptosis. Mechanistically, UNC569 induces DNA damage-mediated G2/M phase arrest and activates JNK/p38 mitogen-activated protein kinase-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.