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Cell Rep DOI:10.1016/j.celrep.2019.07.021

Small-Molecule and CRISPR Screening Converge to Reveal Receptor Tyrosine Kinase Dependencies in Pediatric Rhabdoid Tumors.

Publication TypeJournal Article
Year of Publication2019
AuthorsOberlick, EM, Rees, MG, Seashore-Ludlow, B, Vazquez, F, Nelson, GM, Dharia, NV, Weir, BA, Tsherniak, A, Ghandi, M, Krill-Burger, JM, Meyers, RM, Wang, X, Montgomery, P, Root, DE, Bieber, JM, Radko, S, Cheah, JH, C Hon, S-Y, Shamji, AF, Clemons, PA, Park, PJ, Dyer, MA, Golub, TR, Stegmaier, K, Hahn, WC, Stewart, EA, Schreiber, SL, Roberts, CWM
JournalCell Rep
Volume28
Issue9
Pages2331-2344.e8
Date Published2019 Aug 27
ISSN2211-1247
Abstract

Cancer is often seen as a disease of mutations and chromosomal abnormalities. However, some cancers, including pediatric rhabdoid tumors (RTs), lack recurrent alterations targetable by current drugs and need alternative, informed therapeutic options. To nominate potential targets, we performed a high-throughput small-molecule screen complemented by a genome-scale CRISPR-Cas9 gene-knockout screen in a large number of RT and control cell lines. These approaches converged to reveal several receptor tyrosine kinases (RTKs) as therapeutic targets, with RTK inhibition effective in suppressing RT cell growth in vitro and against a xenograft model in vivo. RT cell lines highly express and activate (phosphorylate) different RTKs, creating dependency without mutation or amplification. Downstream of RTK signaling, we identified PTPN11, encoding the pro-growth signaling protein SHP2, as a shared dependency across all RT cell lines. This study demonstrates that large-scale perturbational screening can uncover vulnerabilities in cancers with "quiet" genomes.

DOI10.1016/j.celrep.2019.07.021
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/31461650?dopt=Abstract

Alternate JournalCell Rep
PubMed ID31461650