Antitumor activity and combined inhibitory effect of ceritinib with gemcitabine in pancreatic cancer

Abstract

Pancreatic cancer (PC) is predominantly incurable and is primarily treated with gemcitabine, but drug resistance commonly develops. Thus, new medicines are needed. Ceritinib (LDK378) is a second-generation tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) with antitumor activity in various cancers. However, studies involving ceritinib for the treatment of PC are inadequate. We analyzed the combined effects of ceritinib and gemcitabine on PC and their mechanism of action. Three PC cell lines were used to evaluate the antitumor effects of ceritinib combined with gemcitabine. We analyzed cell viability using CCK-8 assays, determined apoptosis levels through flow cytometry, and analyzed autophagy and cell signaling pathways by Western blotting and tissue array analysis with samples from xenograft models. Ceritinib strongly inhibited the proliferation of PC cells in a dose-dependent manner, induced apoptosis, and inhibited autophagy and cell migration by regulating relevant factors. Ceritinib in combination with gemcitabine exhibited significant growth inhibition and additive antitumor effects in vitro. In vivo, gemcitabine and ceritinib reduced tumor size by up to 30%. In our study, ALK was shown to be highly expressed in various PC cells and tissues. Ceritinib strongly inhibited the levels of activated ALK in PC cells with subsequent effects on the downstream mediators STAT3, AKT, and ERK. In addition, ceritinib inhibited tumor progression in xenograft models. Overall, our research shows that ceritinib inhibits the ALK signaling pathway, leading to cell growth/angiogenesis inhibition in PC and the induction of apoptosis. We recommend using ceritinib as a new treatment for PC. NEW & NOTEWORTHY These data proved that ceritinib inhibits the anaplastic lymphoma kinase signaling pathway, leading to cell growth/angiogenesis inhibition and the induction of apoptosis by inhibiting STAT3, AKT, and ERK pathway in pancreatic cancer (PC). We recommend using ceritinib as a new treatment for PC.