In silico identification of drug target pathways in breast cancer subtypes using pathway cross-talk inhibition

Claudia Cava, Gloria Bertoli, Isabella Castiglioni

Despite great development in genome and proteome high-throughput methods, treatment failure is a critical point in the management of most solid cancers, including breast cancer (BC). Multiple alternative mechanisms upon drug treatment are involved to offset therapeutic effects, eventually causing drug resistance or treatment failure. Here, we optimized a computational method to discover novel drug target pathways in cancer subtypes using pathway cross-talk inhibition (PCI). The in silico method is based on the detection and quantification of the pathway cross-talk for distinct cancer subtypes. From a BC data set of The Cancer Genome Atlas, we have identified different networks of cross-talking pathways for different BC subtypes, validated using an independent BC dataset from Gene Expression Omnibus. Then, we predicted in silico the effects of new or approved drugs on different BC subtypes by silencing individual or combined subtype-derived pathways with the aim to find new potential drugs or more effective synergistic combinations of drugs. Overall, we identified a set of new potential drug target pathways for distinct BC subtypes on which therapeutic agents could synergically act showing antitumour effects and impacting on cross-talk inhibition. We believe that in silico methods based on PCI could offer valuable approaches to identifying more tailored and effective treatments in particular in heterogeneous cancer diseases.