Ticagrelor inhibits the growth of lung adenocarcinoma by downregulating SYK expression and modulating the PI3K/AKT pathway

Lung cancer is one of the malignant tumors with the highest morbidity and mortality in China. Despite the use of some targeted therapies in lung cancer treatment, the prognosis remains suboptimal, highlighting the urgent need for new, effective drugs to enhance outcomes. Ticagrelor, a marketed anti-platelet drug, has been reported to have anti-tumor effects. This study primarily investigates the inhibitory effect of Ticagrelor on lung adenocarcinoma in both in vivo and in vitro models, as well as its molecular mechanisms. Firstly, the effects of ticagrelor on the proliferation (CCK-8 and Edu staining), migration (scratch test), and invasion (Transwell chamber) of lung adenocarcinoma cells were evaluated using a variety of lung adenocarcinoma cell models. Secondly, the efficacy of ticagrelor on lung adenocarcinoma in vivo was evaluated by A549, H1975 tumor-bearing mouse models. Finally, transcriptomic sequencing (RNA-Seq) and immunohistochemistry were used to explore the molecular mechanism of the intervention effect of ticagrelor on lung cancer. Ticagrelor significantly inhibits the proliferation, migration and invasion of various lung cancer cells in vitro, and markedly suppressed tumor growth in A549 and NCI-H1975 CDX model in vivo. The pathological results showed that the number of tumor cells in the intervention group was significantly reduced, with large area necrosis, and the expression of Ki-67 in the intervention group was significantly decreased by immunohistochemistry. RNA-seq sequencing results from NCI-H1975 xenograft showed that several integrin-related pathways were down-regulated in the Ticagrelor treatment group, along with a significant reduction in spleen tyrosine kinase (SYK), a pivotal protein related to integrin signaling. Furthermore, we demonstrated that ticagrelor inhibits lung adenocarcinoma by down-regulating SYK and regulating PI3K/AKT pathway using WB. Ticagrelor has obvious inhibitory effect on a variety of lung adenocarcinoma cell lines and cell line transplanted tumors, and its antitumor effect may be related to the inhibition of SYK signaling pathway and PI3K/AKT pathway.