Abstract A57: Effects of pre-exposure to siRNA on silencing response: Do cells become resistant to siRNA silencing?

Development of resistance against cytotoxic effect of different generations of anticancer drugs is considered inevitable and remains a major concern for cancer therapy. An alternative therapeutic approach based on protein silencing via RNA interference (RNAi) have shown considerable promise; however, our information about the factors affecting siRNA efficiency and the limitations to their efficacy are limited. This study focused on determining the possibility of development of resistance against siRNA treatment as a result of repeated exposure to siRNA that could affect cellular internalization of the particles, silencing efficiency at mRNA level, and ultimately, the observed cellular response. Two approaches to siRNA exposure were undertaken: one involving a single high concentration exposure to eradicate siRNA-responsive cells, and one involving multiple exposures with a gradually increasing siRNA concentration to study the potential intracellular adaptations. Our results demonstrated a temporary decrease in silencing efficiency at mRNA level without significant alteration in siRNA cellular uptake. We conclude that cells would respond to repeated siRNA exposure in a similar fashion after a temporary initial alteration; however, we could not rule out the possibility of a change in phenotypical response (e.g., number of viable cells) as a result of adjustments in (or selection of cells reliant on) alternative pathways. Citation Format: Hamidreza Montazeri Aliabadi, Parvin Mahdipoor, Cezary Kucharsky, Nicole Chan, Hasan Uludag. Effects of pre-exposure to siRNA on silencing response: Do cells become resistant to siRNA silencing? [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A57.