Abstract 5880: Acquired chemotherapeutic drug resistance in colorectal cancer is regulated by epithelial-to-mesenchymal transition and altered cellular pathways

Abstract

Abstract Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death in the western world. Chemotherapy is the mainstay in the treatment of metastasized CRC. However, cancer cells acquire resistance to treatment by various mechanisms resulting in treatment failure. Even though the molecular mechanisms regulating acquired drug resistance is critical to overcome chemoresistance, it is poorly understood. We developed a panel of seven CRC cells resistant to 5-FU. The parental and 5-FU resistant CRC cells were assayed for proteins known for their involvement in chemotherapeutic resistance. In addition, an unbiased quantitative proteomics and DNA methylation analysis was performed on the panel of seven parental and 5-FU resistant CRC cells. The integrated analysis revealed multiple mechanisms contributing to chemotherapeutic drug resistance including epithelial-to-mesenchymal transition (EMT), deregulation of apoptosis, increased survival autophagy and epigenetic modifications resulting in altered drug metabolite potency. Inhibitors of EMT and autophagy sensitized the 5-FU resistant CRC cells. Furthermore, CRIPSR based gene knockouts of these candidate genes (both up and downregulated) either sensitized the CRC cells or rendered them resistant to 5-FU. As a follow up, PDX mouse models were established and made resistant to 5-FU. Follow up quantitative proteomics and biochemical validations of 5-FU resistant PDX tissue lysates confirmed the role of EMT in acquired chemoresistance. Overall, this project unravelled multiple mechanisms by which CRC cells may become resistant to 5-FU. Importantly, some of these mechanisms are also conserved in many cancer types and hence targeting these mechanisms can overcome chemoresistance and increase patient survival rates. Citation Format: Lahiru Gangoda, Nidhi Mathew, Michael Liem, Shiva Keertikumar, Ching-Seng Ang, John Mariadason, Suresh Mathivanan. Acquired chemotherapeutic drug resistance in colorectal cancer is regulated by epithelial-to-mesenchymal transition and altered cellular pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5880. doi:10.1158/1538-7445.AM2017-5880