Synergistic drug combinations for cancer identified in a CRISPR screen for pairwise genetic interactions

By Kyuho Han, E. Jeng, Gaelen T. Hess, D. Morgens, Amy Li, Michael C. Bassik. 2017

473 citations recorded by the source corpus.

Identification of effective combination therapies is critical to address the emergence of drug-resistant cancers, but direct screening of all possible drug combinations is infeasible. Here we introduce a CRISPR-based double knockout (CDKO) system that improves the efficiency of combinatorial genetic screening using an effective strategy for cloning and sequencing paired single guide RNA (sgRNA) libraries and a robust statistical scoring method for calculating genetic interactions (GIs) from CRISPR-deleted gene pairs. We applied CDKO to generate a large-scale human GI map, comprising 490,000 double-sgRNAs directed against 21,321 pairs of drug targets in K562 leukemia cells and identified synthetic lethal drug target pairs for which corresponding drugs exhibit synergistic killing. These included the BCL2L1 and MCL1 combination, which was also effective in imatinib-resistant cells. We further validated this system by identifying known and previously unidentified GIs between modifiers of ricin toxicity. This work provides an effective strategy to screen synergistic drug combinations in high-throughput and a CRISPR-based tool to dissect functional GI networks.

Subfields: Biotechnology, Molecular Biology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. Marinka Zitnik
2. Jure Leskovec
3. Min Wu
4. Mengyuan Huang
5. Monica Agrawal
6. Hongyi Li
7. Xia Zhao
8. Yang Yang

Citations in the corpus

• Modeling polypharmacy side effects with graph convolutional networks (2018, background): “Most human diseases are caused by complex biological processes that are resistant to the activity of any single drug (Jia et al. , 2009; Han et al. , 2017).”
• Applications of genome editing technology in the targeted therapy of human diseases: mechanisms, advances and prospects (2020, methodology): “A CRISPR-based double-knockout system combined with deep sequencing, phenotypic measurement and genetic analysis has identified interactions between the Signal Transduction and Targeted Therapy (2020) 5:1 synergistic drug targets in K562 leukemia cells, such as BCL2L1 and MCL1.”