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

Citation:

Oberlick 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, Hon S-YC, Shamji AF, Clemons PA, Park PJ, Dyer MA, Golub TR, Stegmaier K, Hahn WC, Stewart EA, Schreiber SL, Roberts CWM. Small-Molecule and CRISPR Screening Converge to Reveal Receptor Tyrosine Kinase Dependencies in Pediatric Rhabdoid Tumors. Cell Rep 2019;28(9):2331-2344.e8. Copy at http://www.tinyurl.com/y5y7t8vk

Date Published:

2019 08 27

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.

Last updated on 10/05/2020