Prediction of Synergistic Drug Combinations for Prostate Cancer by Transcriptomic and Network Characteristics

Prostate cancer (PRAD) is a major cause of cancer-related deaths. Current monotherapies show limited efficacy due to often rapidly emerging resistance. Combination therapies could provide an alternative solution to address this problem with enhanced therapeutic effect, reduced cytotoxicity, and delayed the appearance of drug resistance. However, it is prohibitively cost and labor-intensive for the experimental approaches to pick out synergistic combinations from the millions of possibilities. Thus, it is highly desired to explore other efficient strategies to assist experimental researches. Inspired by the challenge, we construct the transcriptomics-based and network-based prediction models to quickly screen the potential drug combination for PRAD, and further assess their performance by in vitro assays. The transcriptomics-based method screens nine possible combinations. However, the network-based method gives discrepancies for at least three drug pairs. Further experimental results indicate the dose-dependent effects of the three docetaxel-containing combinations, and confirm the synergistic effects of the other six combinations predicted by the transcriptomics-based model. For the network-based predictions, in vitro tests give opposite results to the two combinations (i.e. mitoxantrone-cyproheptadine and cabazitaxel-cyproheptadine). Namely, the transcriptomics-based method outperforms the network-based one for the specific disease like PRAD, which provide guideline for selection of the computational methods in the drug combination screening. More importantly, six combinations (the three mitoxantrone-containing and the three cabazitaxel-containing combinations) are found to be promising candidates to synergistically conquer PRAD.