RESUMEN
Anaplastic lymphoma kinase (ALK) is known to be an important therapeutic target in various types of cancer. NVPTAE684, a wellknown inhibitor of ALK, was revealed to exert antitumor effects in several different malignancies. However, the molecular mechanisms responsible for these antitumor effects in cancer cells, including pancreatic adenocarcinoma cells, remain unknown. In the present study, NVPTAE684 was investigated for its antitumor effects towards pancreatic adenocarcinoma cells. MTT assay, western blot analysis, flow cytometry, caspase3/7 activity assay and Trypan blue exclusion assay were used and it was revealed that NVPTAE684 suppressed the proliferation of seven human pancreatic adenocarcinoma cell lines (AsPC1, Panc1, MIA PaCa2, Capan1, CFPAC1, Colo357 and BxPC3), and significantly increased G2/M arrest and apoptotic cell death. Furthermore, NVPTAE684 inhibited the phosphorylation of ALK at Y1604, as well as that of downstream mediators such as AKT (S473) and ERK1/2 (Y202/T204). Notably, knocking down ALK with siRNAs also decreased proliferation and promoted G2/M arrest and apoptosis. Furthermore, inhibition of ALK with NVPTAE684 or siRNA synergistically enhanced gemcitabineinduced cell death by inducing apoptosis. In conclusion, the findings of the present study indicated that NVPTAE684 exerted its antitumor effects by inducing G2/M arrest and apoptosis via the inhibition of the ALK signaling pathway, and suggests its potential use as an antitumor agent against pancreatic adenocarcinoma.