Lung adenocarcinoma is an aggressive form of cancer that is frequently resistant to frontline platinum chemotherapy, with a response rate below 30%. Inherent resistance to chemotherapy often involves complex signalling networks, and we have recently performed a genome-wide siRNA screen that identified a number of kinase signalling pathways strongly implicated in platinum resistance (Marini et al, Science Translational Medicine, 2018).
Using magnetic bead-based multiplexing technology, we have now profiled the cisplatin-induced signalling dynamics of the PI3K/mTOR, MAPK, SMAD, STAT and NF-κB pathways alongside key apoptosis mediators and DNA damage response proteins in a panel of lung adenocarcinoma cell lines. A multidimensional analysis of this dataset identified a correlation between platinum resistance and elevated P70S6K activity, which directly opposed a late phase, double-strand break DNA damage response that occurred in platinum sensitive cell lines.
Analysis of patient samples revealed that P70S6K is amplified within ~5% of lung adenocarcinomas, with elevated expression also associated with poor patient survival. Furthermore, inhibition of P70S6K in platinum-resistant cell lines with the dual PI3K/mTOR inhibitor dactolisib promoted an increase in the double-strand DNA damage response and restored sensitivity to platinum chemotherapy both in vitro and in vivo.
Therefore, this study is a demonstration of how the early phases of a signalling response can be used to predict the eventual cellular outcome, and subsequently applied to a clinical setting. We have also identified a potential therapeutic strategy in targeting P70S6K to overcome platinum resistance in lung adenocarcinoma.