Integrated Network Pharmacology Approach for Drug Combination Discovery: A Multi-Cancer Case Study

Simple Summary Current treatments for complex diseases, including cancer, are generally characterized by high toxicity due to their low selectivity for target cells. Moreover, patients often develop drug resistance, hence becoming less sensitive to the therapy. For this reason, novel, improved, and more specific pharmacological therapies are needed. The high cost and the time required to develop new drugs poses the attention on the development of computational methods for drug repositioning and combination therapy prediction. In this study, we developed an integrated network pharmacology framework that combines mechanistic and chemocentric approaches in order to predict potential drug combinations for cancer therapy. We applied our paradigm in five cancer types, which we used as case studies. Our strategy can be applied to the study of any complex disease by guiding the prioritization of drug combinations. Despite remarkable efforts of computational and predictive pharmacology to improve therapeutic strategies for complex diseases, only in a few cases have the predictions been eventually employed in the clinics. One of the reasons behind this drawback is that current predictive approaches are based only on the integration of molecular perturbation of a certain disease with drug sensitivity signatures, neglecting intrinsic properties of the drugs. Here we integrate mechanistic and chemocentric approaches to drug repositioning by developing an innovative network pharmacology strategy. We developed a multilayer network-based computational framework integrating perturbational signatures of the disease as well as intrinsic characteristics of the drugs, such as their mechanism of action and chemical structure. We present five case studies carried out on public data from The Cancer Genome Atlas, including invasive breast cancer, colon adenocarcinoma, lung squamous cell carcinoma, hepatocellular carcinoma and prostate adenocarcinoma. Our results highlight paclitaxel as a suitable drug for combination therapy for many of the considered cancer types. In addition, several non-cancer-related genes representing unusual drug targets were identified as potential candidates for pharmacological treatment of cancer.