Current drug treatments have proven ineffective in pancreatic ductal adenocarcinoma (PDAC) as chemoresistance is a common occurrence in this disease. In order to improve survival rates, a combination treatment regimen of anti-cancer drugs will most likely be needed. The oncogenic serine/threonine PIM kinase family has been shown to regulate drug resistance in various cancers, including pancreatic cancer. Several PIM kinase inhibitors have been developed over the years and tested against a number of cancers, including solid tumors. Previous studies in our laboratory have shown a potential synergistic effect on cell viability of PDAC cells when treated with the PIM kinase inhibitor SGI-1776 and gemcitabine. Unfortunately, due to medical problems occurring during Phase I clinical trials , clinical studies using SGI-1776 were terminated. This led to the development by Tolero Pharmaceuticals of a more selective second generation PIM kinase inhibitor, TP-3654. However, to our knowledge no research has been conducted on the interaction of TP-3654 with gemcitabine or other FDA-approved chemotherapeutics. To address this concern, a 384-well high-content cell viability assay was designed to assess synergism between TP-3654 and the National Cancer Institute (NCI) catalog of 88 FDA-approved chemotherapeutics. Using high-content automated microscopy and image analysis, we acquired total cell counts and other important cellular data, such as nuclear and cell morphology. While some drug combinations with TP-3654 proved ineffective, decreased cell viability was observed in several drug classes, including hormonal agents, mTOR inhibitors, and alkylating agents. Compounds causing significant cytotoxicity in combination with TP-3654 were further evaluated to not only confirm synergism, but to potentially understand the cellular mechanisms and signaling pathways involved. Additional studies will include testing TP-3654 with non-chemotherapeutic compounds and purified natural products. The results of these studies could be used to help develop better drug combination strategies to treat pancreatic cancer and increase the survival rate of patients.

Citation Format: Brittany K. Nixon, Qingping He, Vandana Singh, Sarah A. Compton, Steve Warner, David Bearss, Jonathan Z. Sexton, Antonio T. Baines.{Authors}. Pharmacological inhibition of PIM kinases in combination with chemotherapeutic drugs decreases cell viability of pancreatic cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A49.