Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling

McDermott, U., Sharma, S. V., Dowell, L., Greninger, P., Montagut, C., Lamb, J., Archibald, H., Raudales, R., Tam, A., Lee, D., Rothenberg, S. M., Supko, J. G., Sordella, R., Ulkus, L. E., Iafrate, A. J., Maheswaran, S., Njauw, C. N., Tsao, H., Drew, L., Hanke, J. H., Ma, X. J., Erlander, M. G., Gray, N. S., Haber, D. A., Settleman, J. (December 2007) Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling. Proceedings of the National Academy of Sciences of the United States of America, 104 (50). pp. 19936-41. ISSN 0027-8424

PDF (Paper) Identification of genotype-correlated sensitivity.pdf - Published Version Restricted to Repository staff only Download (305kB)

Abstract

Kinase inhibitors constitute an important new class of cancer drugs, whose selective efficacy is largely determined by underlying tumor cell genetics. We established a high-throughput platform to profile 500 cell lines derived from diverse epithelial cancers for sensitivity to 14 kinase inhibitors. Most inhibitors were ineffective against unselected cell lines but exhibited dramatic cell killing of small nonoverlapping subsets. Cells with exquisite sensitivity to EGFR, HER2, MET, or BRAF kinase inhibitors were marked by activating mutations or amplification of the drug target. Although most cell lines recapitulated known tumor-associated genotypes, the screen revealed low-frequency drug-sensitizing genotypes in tumor types not previously associated with drug susceptibility. Furthermore, comparing drugs thought to target the same kinase revealed striking differences, predictive of clinical efficacy. Genetically defined cancer subsets, irrespective of tissue type, predict response to kinase inhibitors, and provide an important preclinical model to guide early clinical applications of novel targeted inhibitors.

Item Type:	Paper
Uncontrolled Keywords:	Antineoplastic Agents/ pharmacology/therapeutic use Cell Line, Tumor Drug Resistance, Neoplasm/ drug effects/genetics Drug Screening Assays, Antitumor Gene Expression Regulation, Neoplastic/ drug effects Genotype Humans Neoplasms/ drug therapy/ enzymology/genetics Protein Kinase Inhibitors/ pharmacology/therapeutic use
Subjects:	diseases & disorders > cancer therapies organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line diseases & disorders > cancer > drugs and therapies organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cell bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase
CSHL Authors:	Sordella, Raffaella
Communities:	CSHL labs > Sordella lab
Depositing User:	CSHL Librarian
Date:	11 December 2007
Date Deposited:	09 Nov 2011 21:32
Last Modified:	13 Mar 2013 15:41
PMCID:	PMC2148401
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/23096

Actions (login required)

Administrator's edit/view item