Small-Molecule and CRISPR Screening Converge to Reveal Receptor Tyrosine Kinase Dependencies in Pediatric Rhabdoid Tumors
Elaine M. Oberlick,
Matthew G. Rees,
Brinton Seashore-Ludlow,
Francisca Vazquez,
Geoffrey M. Nelson,
Neekesh V. Dharia,
Barbara A. Weir,
Aviad Tsherniak,
Mahmoud Ghandi,
John M. Krill-Burger,
Robin M. Meyers,
Xiaofeng Wang,
Phil Montgomery,
David E. Root,
Jake M. Bieber,
Sandi Radko,
Jaime H. Cheah,
C. Suk-Yee Hon,
Alykhan F. Shamji,
Paul A. Clemons,
Peter J. Park,
Michael A. Dyer,
Todd R. Golub,
Kimberly Stegmaier,
William C. Hahn,
Elizabeth A. Stewart,
Stuart L. Schreiber,
Charles W.M. Roberts
Affiliations
Elaine M. Oberlick
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
Matthew G. Rees
Broad Institute, Cambridge, MA 02142, USA; Corresponding author
Brinton Seashore-Ludlow
Broad Institute, Cambridge, MA 02142, USA; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institute, 171 77 Stockholm, Sweden
Francisca Vazquez
Broad Institute, Cambridge, MA 02142, USA
Geoffrey M. Nelson
Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA
Neekesh V. Dharia
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
Barbara A. Weir
Broad Institute, Cambridge, MA 02142, USA
Aviad Tsherniak
Broad Institute, Cambridge, MA 02142, USA
Mahmoud Ghandi
Broad Institute, Cambridge, MA 02142, USA
John M. Krill-Burger
Broad Institute, Cambridge, MA 02142, USA
Robin M. Meyers
Broad Institute, Cambridge, MA 02142, USA
Xiaofeng Wang
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Phil Montgomery
Broad Institute, Cambridge, MA 02142, USA
David E. Root
Broad Institute, Cambridge, MA 02142, USA
Jake M. Bieber
Broad Institute, Cambridge, MA 02142, USA
Sandi Radko
Comprehensive Cancer Center and Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Jaime H. Cheah
Broad Institute, Cambridge, MA 02142, USA
C. Suk-Yee Hon
Broad Institute, Cambridge, MA 02142, USA
Alykhan F. Shamji
Broad Institute, Cambridge, MA 02142, USA
Paul A. Clemons
Broad Institute, Cambridge, MA 02142, USA
Peter J. Park
Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Harvard Ludwig Center, Harvard Medical School, Boston, MA 02115, USA
Michael A. Dyer
Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Todd R. Golub
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
Kimberly Stegmaier
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
William C. Hahn
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
Elizabeth A. Stewart
Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Stuart L. Schreiber
Broad Institute, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA
Charles W.M. Roberts
Comprehensive Cancer Center and Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; Corresponding author
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. : Using a diverse set of rhabdoid tumor cell lines and both small-molecule and CRISPR-Cas9 gene-knockout screening, Oberlick et al. find high expression and dependency upon a wide range of receptor tyrosine kinases (RTKs) and SHP2 downstream. These RTK inhibitors are also effective against a rhabdoid tumor mouse model. Keywords: rhabdoid tumors, SMARCB1, high-throughput drug screening, genome-wide CRISPR screening, receptor tyrosine kinase, PTPN11
