Preclinical pharmacodynamics evaluation of a new Src/FOSL1 inhibitor, LY-1816, in pancreatic ductal adenocarcinoma.

Despite tremendous efforts, the clinical prognosis of pancreatic ductal adenocarcinoma (PDAC) remains disappointing. There is an urgent need to develop more effective treatment strategies to improve the prognosis of patients with PDAC. In this study, we evaluate the anti-PDAC effects of LY-1816, a new multikinase inhibitor developed by us. In in vitro assays, LY-1816 showed significant inhibitory effects on the proliferation, migration, and invasion of human PDAC cells, and induced PDAC cell apoptosis. Western blot analysis revealed that LY-1816 markedly suppressed the Src signaling, and downregulated the expression of FOSL1; FOSL1 is an oncogene vulnerability in KRAS-driven pancreatic cancer. In in vivo models of PDAC xenografts (Aspc-1 and Bxpc-3), LY-1816 showed more potent antitumor activity than dasatinib and gemcitabine. Moreover, mice treated with LY-1816 showed a much more significant survival advantage in a metastatic model of PDAC compared with those treated with vehicle, dasatinib, or gemcitabine. These results provide effective support for the subsequent clinical evaluation of LY-1816 in the treatment of PDAC.