Polypharmacology in Precision Oncology: Current Applications and Future Prospects

Abstract

Over the past decade, a more comprehensive, large-scale approach to studying cancer genetics and biology has revealed the challenges of tumor heterogeneity, adaption, evolution and drug resistance, while systems-based pharmacology and chemical biology strategies have uncovered a much more complex interaction between drugs and the human proteome than was previously anticipated. In this mini-review we assess the progress and potential of drug polypharmacology in biomarker-driven precision oncology. Polypharmacology not only provides great opportunities for drug repurposing to exploit off-target effects in a new single-target indication but through simultaneous blockade of multiple targets or pathways offers exciting opportunities to slow, overcome or even prevent inherent or adaptive drug resistance. We highlight the many challenges associated with exploiting known or desired polypharmacology in drug design and development, and assess computational and experimental methods to uncover unknown polypharmacology. A comprehensive understanding of the intricate links between polypharmacology, efficacy and safety is urgently needed if we are to tackle the enduring challenge of cancer drug resistance and to fully exploit polypharmacology for the ultimate benefit of cancer patients.

Keywords: Polypharmacology; biomarker; multi-target drug design.; off-target; precision oncology; side-effects; systems pharmacology; target profiling.

Fig. (1)

Drug-Target network. Drugs (circles) from Table 1 and targets (rounded rectangles) within 10-fold selectivity from a target clinically validated with a biomarker based on information from the knowledgebase canSAR [48]. Node size and edge width are proportional to the clinical validation based on data available in Table 1. As it can be observed, the off-targets being clinically investigated to extend the uses of these drugs are a minority of all the targets already known to be inhibited by these drugs.