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

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

  • Cell Rep. 2019 Aug 27;28(9):2331-2344.e8. doi: 10.1016/j.celrep.2019.07.021.
Elaine M Oberlick 1,  Matthew G Rees 2,  Brinton Seashore-Ludlow 3,  Francisca Vazquez 4,  Geoffrey M Nelson 5,  Neekesh V Dharia 6,  Barbara A Weir 4,  Aviad Tsherniak 4,  Mahmoud Ghandi 4,  John M Krill-Burger 4,  Robin M Meyers 4,  Xiaofeng Wang 7,  Phil Montgomery 4,  David E Root 4,  Jake M Bieber 4,  Sandi Radko 8,  Jaime H Cheah 4,  C Suk-Yee Hon 4,  Alykhan F Shamji 4,  Paul A Clemons 4,  Peter J Park 9,  Michael A Dyer 10,  Todd R Golub 11,  Kimberly Stegmaier 12,  William C Hahn 13,  Elizabeth A Stewart 10,  Stuart L Schreiber 14,  Charles W M Roberts 15
Affiliations

Affiliations

  • 1 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02142, USA.
  • 2 Broad Institute, Cambridge, MA 02142, USA. Electronic address: reesm@broadinstitute.org.
  • 3 Broad Institute, Cambridge, MA 02142, USA; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institute, 171 77 Stockholm, Sweden.
  • 4 Broad Institute, Cambridge, MA 02142, USA.
  • 5 Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
  • 6 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02215, USA; Boston Children's Hospital, Boston, MA 02115, USA.
  • 7 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 8 Comprehensive Cancer Center and Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 9 Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Harvard Ludwig Center, Harvard Medical School, Boston, MA 02115, USA.
  • 10 Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 11 Broad Institute, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02215, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 12 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA; Boston Children's Hospital, Boston, MA 02115, USA.
  • 13 Broad Institute, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • 14 Broad Institute, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
  • 15 Comprehensive Cancer Center and Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: charles.roberts@stjude.org.
PMID: 31461650 DOI: 10.1016/j.celrep.2019.07.021
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.

Keywords

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

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