Integrated genetic and pharmacologic interrogation of rare cancers
| Autor: | Brian D. Crompton, Jesse S. Boehm, Levi A. Garraway, Paul Van Hummelen, Alykhan F. Shamji, Sara Howell, Craig M. Bielski, Gregory V. Kryukov, Stephanie C. Meyer, William C. Hahn, Yuen-Yi Tseng, Paula Keskula, Coyin Oh, Oliver Jonas, Carlos Rodriguez-Galindo, Shubhroz Gill, Robert Langer, Francisca Vazquez, Mihir B. Doshi, Paul A. Clemons, Alanna J. Church, Andrew L. Hong, Stuart L. Schreiber, Alma Imamovic, Charles W. M. Roberts, Katherine A. Janeway, Michael J. Cima, Kimberly Stegmaier, Aviad Tsherniak, David E. Root, Glenn S. Cowley, Jaime H. Cheah, Bryan D. Kynnap |
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| Přispěvatelé: | Massachusetts Institute of Technology. Department of Materials Science and Engineering, Koch Institute for Integrative Cancer Research at MIT, Jonas, Oliver H., Cheah, Jaime H, Cima, Michael J, Langer, Robert S |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Somatic cell Pyridines Druggability General Physics and Astronomy Receptors Cytoplasmic and Nuclear Bioinformatics Piperazines Mice RNA interference Antineoplastic Combined Chemotherapy Protocols Exome Neoplasm Metastasis Multidisciplinary Cell Cycle Sarcoma Genomics 3. Good health Hydrazines Female RNA Interference Functional genomics Science Mice Nude Biology Karyopherins General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Rare Diseases Cell Line Tumor medicine Animals Humans Sequence Analysis RNA Cancer Cyclin-Dependent Kinase 4 General Chemistry Triazoles medicine.disease 030104 developmental biology A549 Cells Doxorubicin CRISPR-Cas Systems Drug Screening Assays Antitumor Neoplasm Recurrence Local Neoplasm Transplantation |
| Zdroj: | Nature Communications Nature Communications, Vol 7, Iss 1, Pp 1-9 (2016) Nature |
| ISSN: | 2041-1723 |
| Popis: | 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. Identifying therapeutic targets in rare cancers is challenging due to the lack of relevant pre-clinical models. Here, the authors generate a cancer cell line from a paediatric patient with a rare undifferentiated sarcoma and through functional genomics and chemical screens identified CDK4 and XPO1 as potential therapeutic targets in this cancer. |
| Databáze: | OpenAIRE |
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