Integrated genetic and pharmacologic interrogation of rare cancers
| Title: | Integrated genetic and pharmacologic interrogation of rare cancers |
| Author: |
Hong, Andrew L.; Tseng, Yuen-Yi; Cowley, Glenn S.; Jonas, Oliver; Cheah, Jaime H.; Kynnap, Bryan D.; Doshi, Mihir B.; Oh, Coyin; Meyer, Stephanie C.; Church, Alanna J.; Gill, Shubhroz; Bielski, Craig M.; Keskula, Paula; Imamovic, Alma; Howell, Sara; Kryukov, Gregory V.; Clemons, Paul A.; Tsherniak, Aviad; Vazquez, Francisca; Crompton, Brian D.; Shamji, Alykhan F.; Rodriguez-Galindo, Carlos; Janeway, Katherine A.; Roberts, Charles W. M.; Stegmaier, Kimberly; van Hummelen, Paul; Cima, Michael J.; Langer, Robert S.; Garraway, Levi A.; Schreiber, Stuart L.; Root, David E.; Hahn, William C.; Boehm, Jesse S.
Note: Order does not necessarily reflect citation order of authors. |
| Citation: | Hong, A. L., Y. Tseng, G. S. Cowley, O. Jonas, J. H. Cheah, B. D. Kynnap, M. B. Doshi, et al. 2016. “Integrated genetic and pharmacologic interrogation of rare cancers.” Nature Communications 7 (1): 11987. doi:10.1038/ncomms11987. http://dx.doi.org/10.1038/ncomms11987. |
| Full Text & Related Files: |
4917959.pdf (1.056Mb; PDF) 
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| Abstract: | Identifying therapeutic targets in rare cancers remains challenging due to the paucity of established models to perform preclinical studies. As a proof-of-concept, we developed a patient-derived cancer cell line, CLF-PED-015-T, from a paediatric patient with a rare undifferentiated sarcoma. Here, we confirm that this cell line recapitulates the histology and harbours the majority of the somatic genetic alterations found in a metastatic lesion isolated at first relapse. We then perform pooled CRISPR-Cas9 and RNAi loss-of-function screens and a small-molecule screen focused on druggable cancer targets. Integrating these three complementary and orthogonal methods, we identify CDK4 and XPO1 as potential therapeutic targets in this cancer, which has no known alterations in these genes. These observations establish an approach that integrates new patient-derived models, functional genomics and chemical screens to facilitate the discovery of targets in rare cancers. |
| Published Version: | doi:10.1038/ncomms11987 |
| Other Sources: | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917959/pdf/ |
| Terms of Use: | This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA |
| Citable link to this page: | http://nrs.harvard.edu/urn-3:HUL.InstRepos:27822296 |
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