Cell Reports
Volume 28, Issue 9, 27 August 2019, Pages 2331-2344.e8
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Article
Small-Molecule and CRISPR Screening Converge to Reveal Receptor Tyrosine Kinase Dependencies in Pediatric Rhabdoid Tumors

https://doi.org/10.1016/j.celrep.2019.07.021Get rights and content
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Highlights

  • Rhabdoid cell lines and tumors have few mutations yet highly express a range of RTKs

  • RTKs and SHP2 are vulnerabilities in small-molecule and CRISPR-knockout screens

  • RTK inhibitors are effective against a xenografted rhabdoid mouse model in vivo

  • Perturbational screens may identify vulnerabilities not detectable in genomic analyses

Summary

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.

Keywords

rhabdoid tumors
SMARCB1
high-throughput drug screening
genome-wide CRISPR screening
receptor tyrosine kinase
PTPN11

Cited by (0)

14

These authors contributed equally

15

Present address: Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA

16

Present address: Department of Molecular & Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Lebanon, NH 03756, USA

17

Present address: Massachusetts General Hospital, Boston, MA 02114, USA

18

Present address: Janssen R&D, Cambridge, MA 02142, USA

19

Lead Contact