Mechanisms and Dynamics Leading to Permanent Drug Resistance

Conducted by Associate Professor Helmut Schaider (UQ DRC DI) and Dr Dinoop Ravindran Menon (UA DRC), in collaboration with Associate Professor Richard Sturm (UQ DRC), Professor H. Peter Soyer (UQ DRC), Associate Professor Nikolas K. Haass (UQ DI), Professor Brian Gabrielli (UQ DI), Dr Victoria Atkinson (UQ PAH) and Professor Meenhard Herlyn (The Wistar Institute, Philadelphia, PA, US)

Aim of the study: To scrutinize mechanisms of acquired drug resistance with emphasis on epigenetic changes, chromatin remodelling, and the dynamics leading to permanent drug resistance. Based on our model of the emergence of permanent drug resistance as a result of stress induced epigenetic remodelling characterized by the expression of certain markers we are investigating into common features of the dynamics leading to permanent drug resistance. These measures will lead identifying new targets and interventions to prevent drug resistance in cancer patients.    

Methods: Cell culture, in vivo xenograft and PDX derived mouse models, microarrays, molecular biology, ChIP sequencing, methylation arrays, RPPAs, IHC from patient tissue, FACS, co-cultures

Description: Disease relapse is a common phenomenon in cancer patients treated with chemotherapy or targeted therapies due to the development of acquired drug resistance. We previously described the occurrence of permanent resistance being a dynamic process of stress induced drug tolerant cells with concomitant epigenetic changes and the expression of certain markers.

Status:  Currently we are studying phenotypically the transition of parental cells into stress induced drug tolerant cancer cells as a result of epigenetic changes. Multi-drug tolerant cells are further characterized for their expression of antigens and immune-checkpoint inhibitors to investigate into immune related interactions.