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Nat Commun DOI:10.1038/ncomms11987

Integrated genetic and pharmacologic interrogation of rare cancers.

Publication TypeJournal Article
Year of Publication2016
AuthorsHong, AL, Tseng, Y-Y, Cowley, GS, Jonas, O, Cheah, JH, Kynnap, BD, Doshi, MB, Oh, C, Meyer, SC, Church, AJ, Gill, S, Bielski, CM, Keskula, P, Imamovic, A, Howell, S, Kryukov, GV, Clemons, PA, Tsherniak, A, Vazquez, F, Crompton, BD, Shamji, AF, Rodriguez-Galindo, C, Janeway, KA, Roberts, CWM, Stegmaier, K, Van Hummelen, P, Cima, MJ, Langer, RS, Garraway, LA, Schreiber, SL, Root, DE, Hahn, WC, Boehm, JS
JournalNat Commun
Date Published2016 Jun 22

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.


Alternate JournalNat Commun
PubMed ID27329820
PubMed Central IDPMC4917959
Grant ListT32 CA136432 / CA / NCI NIH HHS / United States
R25 CA174650 / CA / NCI NIH HHS / United States
U01 CA176152 / CA / NCI NIH HHS / United States
K12 HD052896 / HD / NICHD NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States