Integrated genetic and pharmacologic interrogation of rare cancers

Andrew L. Hong, Yuen-Yi Tseng, Glenn S. Cowley, Oliver Jonas, Jaime H. Cheah, Bryan D. Kynnap, Mihir B. Doshi, Coyin Oh, Stephanie C. Meyer, Alanna J. Church, Shubhroz Gill, Craig M. Bielski, Paula Keskula, Alma Imamovic, Sara Howell, Gregory V. Kryukov, Paul A. Clemons, Aviad Tsherniak, Francisca Vazquez, Brian D. Crompton, Alykhan F. Shamji, Carlos Rodriguez-Galindo, Katherine A. Janeway, Charles W. M. Roberts, Kimberly Stegmaier, Paul van Hummelen, Michael J. Cima, Robert S. Langer, Levi A. Garraway, Stuart L. Schreiber, David E. Root, William C. Hahn () and Jesse S. Boehm ()
Additional contact information
Andrew L. Hong: Boston Children’s Hospital
Yuen-Yi Tseng: Broad Institute of Harvard and MIT
Glenn S. Cowley: Broad Institute of Harvard and MIT
Oliver Jonas: Koch Institute for Integrative Cancer Research at MIT
Jaime H. Cheah: Koch Institute for Integrative Cancer Research at MIT
Bryan D. Kynnap: Dana-Farber Cancer Institute
Mihir B. Doshi: Dana-Farber Cancer Institute
Coyin Oh: Broad Institute of Harvard and MIT
Stephanie C. Meyer: Boston Children’s Hospital
Alanna J. Church: Boston Children’s Hospital
Shubhroz Gill: Broad Institute of Harvard and MIT
Craig M. Bielski: Broad Institute of Harvard and MIT
Paula Keskula: Broad Institute of Harvard and MIT
Alma Imamovic: Dana-Farber Cancer Institute
Sara Howell: Broad Institute of Harvard and MIT
Gregory V. Kryukov: Broad Institute of Harvard and MIT
Paul A. Clemons: Broad Institute of Harvard and MIT
Aviad Tsherniak: Broad Institute of Harvard and MIT
Francisca Vazquez: Broad Institute of Harvard and MIT
Brian D. Crompton: Boston Children’s Hospital
Alykhan F. Shamji: Broad Institute of Harvard and MIT
Carlos Rodriguez-Galindo: Boston Children’s Hospital
Katherine A. Janeway: Boston Children’s Hospital
Charles W. M. Roberts: Boston Children’s Hospital
Kimberly Stegmaier: Boston Children’s Hospital
Paul van Hummelen: Dana-Farber Cancer Institute
Michael J. Cima: Koch Institute for Integrative Cancer Research at MIT
Robert S. Langer: Koch Institute for Integrative Cancer Research at MIT
Levi A. Garraway: Dana-Farber Cancer Institute
Stuart L. Schreiber: Broad Institute of Harvard and MIT
David E. Root: Broad Institute of Harvard and MIT
William C. Hahn: Dana-Farber Cancer Institute
Jesse S. Boehm: Broad Institute of Harvard and MIT

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11987

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