Gene therapy using oncolytic adenoviruses is a novel approach for human cancer therapeutics. The current study aimed to investigate whether the combined use of an adenovirus expressing tumor necrosis factor‑related apoptosis‑inducing ligand (TRAIL) and second mitochondria‑derived activator of caspase (Smac) upon caspase activation (ZD55‑TRAIL‑IETD‑Smac) and cyclin‑dependent kinase (CDK) inhibitor SNS‑032 will synergistically reinforce their anti‑pancreatic cancer activities. The experiments in vitro demonstrated that SNS‑032 enhances ZD55‑TRAIL‑IETD‑Smac‑induced apoptosis and causes marked pancreatic cancer cell death. Western blot assays suggested that the SNS‑032 intensified ZD55‑TRAIL‑IETD‑Smac‑induced apoptosis of pancreatic cancer cells by affecting anti‑apoptotic signaling elements, including CDK‑2, CDK‑9, Mcl‑1 and XIAP. Additionally, animal experiments further confirmed that the combination of SNS‑032 and ZD55‑TRAIL‑IETD‑Smac significantly inhibited the growth of BxPC‑3 pancreatic tumor xenografts. In conclusion, the present study demonstrated that SNS‑032 sensitizes human pancreatic cancer cells to ZD55‑TRAIL‑IETD‑Smac‑induced cell death in vitro and in vivo. These findings indicate that combined treatment with SNS‑032 and ZD55‑TRAIL‑IETD‑Smac could represent a rational approach for anti‑pancreatic cancer therapy.