Functional-genetic approaches to understanding drug response and resistance.

Drug development remains a slow and expensive process, while the effective use of established therapeutics is widely hampered by our limited understanding of response and resistance mechanisms. Functional-genetic tools such as CRISPR/Cas9, advanced RNAi methods, and targeted protein degradation, together with other emerging technologies such as time-resolved and single-cell transcriptomics, fundamentally change the way we can search for candidate therapeutic targets and evaluate them before drug development. In addition, for already available therapeutics these tools open vast opportunities for probing response mechanisms and predictive biomarkers, and thereby guide the development of personalized therapies. Here, we review promising applications and remaining limitations of recently established functional-genetic tools for high-throughput screening and the in-depth analysis of candidate targets and established drugs.