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

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.

journal_name

Cell Rep

journal_title

Cell reports

authors

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 CS,Shamji AF,Clemons PA,Park PJ

doi

10.1016/j.celrep.2019.07.021

subject

Has Abstract

pub_date

2019-08-27 00:00:00

pages

2331-2344.e8

issue

9

issn

2211-1247

pii

S2211-1247(19)30911-8

journal_volume

28

pub_type

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