Computational Pipeline for Rational Drug Combination Screening in Patient-Derived Cells

Abstract

In many complex diseases, such as cancers, resistance to monotherapies easily occurs, and longer-term treatment responses often require combinatorial therapies as next-line regimens. However, due to a massive number of possible drug combinations to test, there is a need for systematic and rational approaches to finding safe and effective drug combinations for each individual patient. This protocol describes an ecosystem of computational methods to guide high-throughput combinatorial screening that help experimental researchers to identify optimal drug combinations in terms of synergy, efficacy, and/or selectivity for further preclinical and clinical investigation. The methods are demonstrated in the context of combinatorial screening in primary cells of leukemia patients, where the translational aim is to identify drug combinations that show not only high synergy but also maximal cancer-selectivity. The mechanism-agnostic and cost-effective computational methods are widely applicable to various cancer types, which are amenable to drug testing, as the computational methods take as input only the phenotypic measurements of a subset of drug combinations, without requiring target information or genomic profiles of the patient samples.

Keywords: Drug combinations; High-throughput screening; Precision oncology; Predictive modeling; Synergy scoring; Toxic effects.