Pan-Pim kinase inhibitor AZD1208 suppresses tumor growth and synergistically interacts with an Akt inhibitor in gastric cancer cells

Abstract

Pim kinases are highly conserved serine/threonine kinases that control proliferation and survival pathways in cancer cells. Different expression patterns of each Pim isoform (Pim-1, Pim-2 and Pim-3) have been observed in various types of human cancer including gastric cancer. AZD1208 is a potent and selective inhibitor that affects all three Pim kinase isoforms. In the present study, we used AZD1208 to demonstrate that inhibition of Pim kinase activity induces gastric cancer cell death. Treatment with AZD1208 alone down-regulated the expression of the Pim kinase substrates, but cell viability in short-term cell cultures was not observed. In long-term cultures, we observed significantly decreased cell viability and up-regulated expression of light chain 3B (LC3B), an autophagy marker, in a dose-dependent manner only in the AZD1208-sensitive cell line. This finding suggested that the cytotoxic effect of AZD1208 was achieved through autophagy and not apoptosis. Moreover, we found that ataxia telangiectasia mutated (ATM) and checkpoint kinase (CHK2), two critical components of the DNA repair pathway, were activated in an AZD1208-resistant cell line. We also confirmed that a combination of an Akt inhibitor with AZD1208 produced a highly synergistic effect in gastric cancer cell lines. Taken together, our data demonstrated that treatment with AZD1208 alone induced considerable cell death through autophagy. Additionally, a combination of Pim and Akt inhibitors had a strongly synergistic effect in human gastric cancer cell lines.