Network-oriented approaches to anticancer drug response

Abstract

A long-standing paradigm in drug discovery has been the concept of designing maximally selective drugs to act on individual targets considered to underlie a disease of interest. Nonetheless, although some drugs have proven to be successful, many more potential drugs identified by the “one gene, one drug, one disease" approach have been found to be less effective than expected or to cause notable side effects. Advances in systems biology and high-throughput in-depth genomic profiling technologies along with an analysis of the successful and failed drugs uncovered that the prominent factor to determine drug sensitivity is the intrinsic robustness of the response of biological systems in the face of perturbations. The complexity of the molecular and cellular bases of systems responses to drug interventions has fostered an increased interest in systems-oriented approaches to drug discovery. Consonant with this knowledge of the multifactorial mechanistic basis of drug sensitivity and resistance is the application of network-based approaches for the identification of molecular (multi-)feature signatures associated with desired (multi-)drug phenotypic profiles. This chapter illustrates the principal network analysis and inference techniques which have found application in systems-oriented drug design and considers their benefits and drawbacks in relation to the nature of the data produced by network pharmacology.