Related Experiment Video
Updated: Jan 20, 2026
Receptor Tyrosine Kinases
Small-Molecule and CRISPR Screening Converge to Reveal Receptor Tyrosine Kinase Dependencies in Pediatric Rhabdoid
Elaine M Oberlick1, Matthew G Rees2, Brinton Seashore-Ludlow3
1Department 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.
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.
Insights
Pediatric rhabdoid tumors (RTs) often lack mutations, but this study found they depend on receptor tyrosine kinases (RTKs). Inhibiting RTKs and SHP2 effectively suppressed RT growth, offering new therapeutic strategies for these difficult cancers.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Pediatric rhabdoid tumors (RTs) frequently lack targetable mutations, necessitating novel therapeutic strategies.
- Understanding the molecular drivers of RTs is crucial for developing effective treatments.
Purpose of the Study:
- To identify novel therapeutic targets in RTs using large-scale screening approaches.
- To uncover vulnerabilities in RTs with genetically "quiet" genomes.
Main Methods:
- Conducted high-throughput small-molecule screening in RT and control cell lines.
- Performed genome-scale CRISPR-Cas9 gene-knockout screens to identify essential genes.
- Utilized in vitro and in vivo xenograft models to assess therapeutic efficacy.
Main Results:
- Convergent screening identified several receptor tyrosine kinases (RTKs) as potential therapeutic targets.
- RTK inhibition demonstrated efficacy in suppressing RT cell growth in vitro and in vivo.
- Identified PTPN11 (SHP2) as a shared downstream dependency in RT cell lines, independent of mutation or amplification.
- RT cell lines exhibit high expression and activation of various RTKs, indicating functional dependency.
Conclusions:
- Large-scale perturbational screening can reveal vulnerabilities in cancers lacking recurrent genetic alterations.
- Targeting RTKs and downstream effectors like SHP2 presents a promising therapeutic avenue for pediatric rhabdoid tumors.
- This study highlights the potential of targeting signaling dependencies in cancers with "quiet" genomes.
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