A CRISPR-drug perturbational map for identifying compounds to combine with commonly used chemotherapeutics

Hyeong-Min Lee, William C. Wright, Min Pan, Jonathan Low, Duane Currier, Jie Fang, Shivendra Singh, Stephanie Nance, Ian Delahunty, Yuna Kim, Richard H. Chapple, Yinwen Zhang, Xueying Liu, Jacob A. Steele, Jun Qi, Shondra M. Pruett-Miller, John Easton, Taosheng Chen, Jun Yang (), Adam D. Durbin () and Paul Geeleher ()
Additional contact information
Hyeong-Min Lee: St. Jude Children’s Research Hospital
William C. Wright: St. Jude Children’s Research Hospital
Min Pan: St. Jude Children’s Research Hospital
Jonathan Low: St. Jude Children’s Research Hospital
Duane Currier: St. Jude Children’s Research Hospital
Jie Fang: St. Jude Children’s Research Hospital
Shivendra Singh: St. Jude Children’s Research Hospital
Stephanie Nance: St. Jude Children’s Research Hospital
Ian Delahunty: St. Jude Children’s Research Hospital
Yuna Kim: St. Jude Children’s Research Hospital
Richard H. Chapple: St. Jude Children’s Research Hospital
Yinwen Zhang: St. Jude Children’s Research Hospital
Xueying Liu: St. Jude Children’s Research Hospital
Jacob A. Steele: St. Jude Children’s Research Hospital
Jun Qi: Dana-Farber Cancer Institute
Shondra M. Pruett-Miller: St. Jude Children’s Research Hospital
John Easton: St. Jude Children’s Research Hospital
Taosheng Chen: St. Jude Children’s Research Hospital
Jun Yang: St. Jude Children’s Research Hospital
Adam D. Durbin: St. Jude Children’s Research Hospital
Paul Geeleher: St. Jude Children’s Research Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Combination chemotherapy is crucial for successfully treating cancer. However, the enormous number of possible drug combinations means discovering safe and effective combinations remains a significant challenge. To improve this process, we conduct large-scale targeted CRISPR knockout screens in drug-treated cells, creating a genetic map of druggable genes that sensitize cells to commonly used chemotherapeutics. We prioritize neuroblastoma, the most common extracranial pediatric solid tumor, where ~50% of high-risk patients do not survive. Our screen examines all druggable gene knockouts in 18 cell lines (10 neuroblastoma, 8 others) treated with 8 widely used drugs, resulting in 94,320 unique combination-cell line perturbations, which is comparable to the largest existing drug combination screens. Using dense drug-drug rescreening, we find that the top CRISPR-nominated drug combinations are more synergistic than standard-of-care combinations, suggesting existing combinations could be improved. As proof of principle, we discover that inhibition of PRKDC, a component of the non-homologous end-joining pathway, sensitizes high-risk neuroblastoma cells to the standard-of-care drug doxorubicin in vitro and in vivo using patient-derived xenograft (PDX) models. Our findings provide a valuable resource and demonstrate the feasibility of using targeted CRISPR knockout to discover combinations with common chemotherapeutics, a methodology with application across all cancers.

Date: 2023
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DOI: 10.1038/s41467-023-43134-0

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