Abstract 3586: The use of kinome profiling to determine potential resistance pathways in pancreatic cancer cells treated with PIM kinase inhibitors

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent cancer of the pancreas with a 5-year survival rate of 6%, making it the 4th most common cause of cancer deaths in the United States. One of the challenges related to this cancer is the issue of chemoresistance. Chemoresistance renders most drugs ineffective in the treatment of PDAC, including kinase inhibitors and the chemotherapeutic drug gemcitabine. PIM (Proviral Integration site for the Moloney murine leukemia virus) kinases are a family of proteins shown to play an important role in the chemoresistance of many cancers, including pancreatic cancer. PIMs act downstream of the JAK-STAT cytokine signaling pathway and phosphorylate substrates involved in numerous cell functions including cell cycle progression and apoptosis. One objective of our research was to determine the role of PIM kinases on transformed phenotypes of PDAC cells. We were able to demonstrate that the PIM kinase inhibitor SGI-1776 and TP-3654, a second generation PIM kinase inhibitor, were able to inhibit growth in cell viability assay. Also, the PIM inhibitors were able to decrease various phenotypes such as anchorage-dependent and anchorage-independent growth in MIA PaCa-2 and PANC-1 cells. A second objective was to determine if PIM kinase inhibitors could reduce chemoresistance in PDAC cells. PIM inhibitors in combination with gemcitabine decreased cell viability in PDAC cells significantly more than when administered separately. To investigate resistance pathways activated in PDAC cells after treatment with PIM kinase inhibitors, we applied multiplexed inhibitor beads (MIBs) mass spectrometry (MS) to profile the kinome. We observed numerous kinases that were downregulated or upregulated after treatment. One of the kinases upregulated was IKKα, a key kinase in the anti-apoptotic NF-κB signaling pathway. Our results suggest that PIM kinases are an important target for cell growth and chemoresistance in pancreatic cancer. Also, these results suggest that treating PDAC cells with a PIM inhibitor simultaneously with an IKK inhibitor might prevent the effects of resistance pathways. Overall, our studies demonstrate that kinome profiling is an effective strategy to identify cellular responses to PIM kinase inhibitors as well as other drugs for treating pancreatic and other cancers. Citation Format: Vandana Singh, Brittany Nixon, T.S. Karim Gilbert, Steve Warner, David Bearss, Lee M. Graves, Antonio T. Baines. The use of kinome profiling to determine potential resistance pathways in pancreatic cancer cells treated with PIM kinase inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3586. doi:10.1158/1538-7445.AM2015-3586