Oberlick EM, Rees MG, Seashore-Ludlow B, Vazquez F, Nelson GM, Dharia NV, Weir BA, Tsherniak A, Ghandi M, Krill-Burger JM, et al. Small-Molecule and CRISPR Screening Converge to Reveal Receptor Tyrosine Kinase Dependencies in Pediatric Rhabdoid Tumors. Cell Rep. 2019;28:2331–2344 e8.
NOTES
Oberlick, Elaine MRees, Matthew GSeashore-Ludlow, BrintonVazquez, FranciscaNelson, Geoffrey MDharia, Neekesh VWeir, Barbara ATsherniak, AviadGhandi, MahmoudKrill-Burger, John MMeyers, Robin MWang, XiaofengMontgomery, PhilRoot, David EBieber, Jake MRadko, SandiCheah, Jaime HHon, C Suk-YeeShamji, Alykhan FClemons, Paul APark, Peter JDyer, Michael AGolub, Todd RStegmaier, KimberlyHahn, William CStewart, Elizabeth ASchreiber, Stuart LRoberts, Charles W MengU01 CA176152/CA/NCI NIH HHS/HHMI/Howard Hughes Medical Institute/R01 CA113794/CA/NCI NIH HHS/F31 CA183558/CA/NCI NIH HHS/U01 CA176058/CA/NCI NIH HHS/P30 CA021765/CA/NCI NIH HHS/U01 CA217848/CA/NCI NIH HHS/R01 CA172152/CA/NCI NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tCell Rep. 2019 Aug 27;28(9):2331-2344.e8. 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.
Last updated on 02/17/2021