Activation of the Anaphase Promoting Complex reverses multiple drug resistant cancer

Abstract

Like humans, canine companions spontaneously develop lymphomas that are treated by a cocktail of chemotherapy drugs. However, canines have high rates of developing multiple drug resistance (MDR), shortened clinical timelines and easy tumor accessibility, making them excellent models to study MDR mechanisms. Previously, we used in vitro cell models to demonstrate that metformin resensitized MDR cells to chemotherapy and prevented MDR development. Here, we used metformin to understand the in vivo molecular mechanisms regulating MDR development and reversal. Metformin was added to chemotherapy in MDR canines, reducing MDR biomarkers within all tumors tested, with one canine entering remission after prior repeated relapses. We employed microarray analyses to identify molecular networks involved in MDR development and the impact of metformin treatement. Tumor sampling throughout entry to remission and subsequent relapse allowed correlation of gene expression profiles to MDR tumor behavior. We discovered that the Anaphase Promoting Complex (APC), a ubiquitin-ligase regulating cell cycle progression, was impaired in MDR samples. In vitro tests demonstrated that APC activation resensitized MDR cells to chemotherapy. The companion canine, therefore, is a powerful translational MDR model that has revealed the APC as an underlying cellular mechanism associated with treatment resistance, and a novel potential therapeutic target.