Abstract 2926: The glycogen synthase kinase-3 inhibitor, 9-ING-41, synergizes with chemotherapy to inhibit pancreatic tumor growth in vivo

Abstract

Abstract Glycogen synthase kinase-3 (GSK3) is a ubiquitously expressed serine-threonine protein kinase involved in multiple cellular functions ranging from the control of glycogen metabolism to transcriptional regulation. We have previously demonstrated that GSK-3β is overexpressed in human pancreatic ductal adenocarcinoma (PDAC) and aberrant nuclear accumulation of GSK-3β serves as a hallmark of poorly differentiated PDAC. Moreover, genetic ablation of GSK-3β or GSK-3 inhibition led to PDAC tumor cell killing, identifying GSK-3β as a therapeutic target in PDAC. Herein, we describe a novel GSK-3 inhibitor, 9-ING-41. The effect of 9-ING-41 on tumor cell growth was tested using several PDAC and patient-derived xenograft (PDX) cell lines in vitro and in vivo using an orthotopic pancreatic cancer animal model. Interestingly, 9-ING-41 treatment resulted in the stabilization of cyclin B levels as well as enhanced serine-10 phosphorylated histone H3 (pS10HH3) and consequently M phase arrest and blocked mitotic exit. The prolonged M phase arrest induced mitotic catastrophe in pancreatic cancer cell lines and inhibited in vitro colony formation. An in vivo orthotopic pancreatic cancer animal model study using PDX-derived cell lines demonstrated that 9-ING-41 hindered tumor growth in combination with several standard chemotherapeutic agents. Significantly, we found that 9-ING-41 treatment impaired the DNA damage response pathway activated by Gemcitabine in pancreatic cancer cell lines. In conclusion, our study indicates that GSK-3 plays an important role in pancreatic cancer progression and 9-ING-41 in combination with existing gemcitabine or irinotecan could be a new strategy for treating patients with PDAC. Citation Format: Li Ding, Jin-san Zhang, John R. Dube, Vijay S. Madamsetty, Daniel M. Schmitt, Debabrata Mukhopadhyay, Daniel D. Billadeau. The glycogen synthase kinase-3 inhibitor, 9-ING-41, synergizes with chemotherapy to inhibit pancreatic tumor growth in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2926.