GSK-3β in Pancreatic Cancer: Spotlight on 9-ING-41, Its Therapeutic Potential and Immune Modulatory Properties

SIMPLE SUMMARY: Glycogen synthase kinase-3 beta is a protein kinase implicated in the promotion and development of various cancers, including pancreatic cancer. In cell culture and animal studies, drugs targeting the inhibition of this protein show treatment potential in pancreatic cancer. Studies show targeting this protein for treatment may overcome resistance to conventional chemotherapy in pancreatic tumors. Early-stage clinical trials are currently studying small molecule inhibitors targeting glycogen synthase kinase-3 beta and interim results show favorable results. Recent studies also suggest that targeting this protein will create synergy with immunotherapy, such as checkpoint inhibitors. Future studies should aim to study new combination treatments involving glycogen synthase kinase-3 beta targeting drugs with chemotherapy and immunotherapy in pancreatic cancer. ABSTRACT: Glycogen synthase kinase-3 beta is a ubiquitously and constitutively expressed molecule with pleiotropic function. It acts as a protooncogene in the development of several solid tumors including pancreatic cancer through its involvement in various cellular processes including cell proliferation, survival, invasion and metastasis, as well as autophagy. Furthermore, the level of aberrant glycogen synthase kinase-3 beta expression in the nucleus is inversely correlated with tumor differentiation and survival in both in vitro and in vivo models of pancreatic cancer. Small molecule inhibitors of glycogen synthase kinase-3 beta have demonstrated therapeutic potential in pre-clinical models and are currently being evaluated in early phase clinical trials involving pancreatic cancer patients with interim results showing favorable results. Moreover, recent studies support a rationale for the combination of glycogen synthase kinase-3 beta inhibitors with chemotherapy and immunotherapy, warranting the evaluation of novel combination regimens in the future.