Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Dharia, NV, Kugener, G, Guenther, LM, Malone, CF, Durbin, AD, Hong, AL, Howard, TP, Bandopadhayay, P, Wechsler, CS, Fung, I, Warren, AC, Dempster, JM, Krill-Burger, JM, Paolella, BR, Moh, P, Jha, N, Tang, A, Montgomery, P, Boehm, JS, Hahn, WC, Roberts, CWM, McFarland, JM, Tsherniak, A, Golub, TR, Vazquez, F, Stegmaier, K |
Journal | Nat Genet |
Volume | 53 |
Issue | 4 |
Pages | 529-538 |
Date Published | 2021 04 |
ISSN | 1546-1718 |
Keywords | Adult, Cell Line, Tumor, Child, Chromosome Mapping, Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR-Associated Protein 9, CRISPR-Cas Systems, Gene Editing, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Genome, Human, Humans, Mutation, Neoplasm Proteins, Neoplasms, RNA, Guide |
Abstract | Exciting therapeutic targets are emerging from CRISPR-based screens of high mutational-burden adult cancers. A key question, however, is whether functional genomic approaches will yield new targets in pediatric cancers, known for remarkably few mutations, which often encode proteins considered challenging drug targets. To address this, we created a first-generation pediatric cancer dependency map representing 13 pediatric solid and brain tumor types. Eighty-two pediatric cancer cell lines were subjected to genome-scale CRISPR-Cas9 loss-of-function screening to identify genes required for cell survival. In contrast to the finding that pediatric cancers harbor fewer somatic mutations, we found a similar complexity of genetic dependencies in pediatric cancer cell lines compared to that in adult models. Findings from the pediatric cancer dependency map provide preclinical support for ongoing precision medicine clinical trials. The vulnerabilities observed in pediatric cancers were often distinct from those in adult cancer, indicating that repurposing adult oncology drugs will be insufficient to address childhood cancers. |
DOI | 10.1038/s41588-021-00819-w |
Pubmed | |
Alternate Journal | Nat Genet |
PubMed ID | 33753930 |
PubMed Central ID | PMC8049517 |
Grant List | T32 GM007226 / GM / NIGMS NIH HHS / United States P01 CA217959 / CA / NCI NIH HHS / United States U01 CA176058 / CA / NCI NIH HHS / United States F32 CA243266 / CA / NCI NIH HHS / United States R00 CA201592 / CA / NCI NIH HHS / United States T32 GM007753 / GM / NIGMS NIH HHS / United States K08 CA245251 / CA / NCI NIH HHS / United States R35 CA210030 / CA / NCI NIH HHS / United States R01 CA204915 / CA / NCI NIH HHS / United States |
Nat Genet DOI:10.1038/s41588-021-00819-w
A first-generation pediatric cancer dependency map.
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