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

Article Details

Citation

McDermott U, Sharma SV, Dowell L, Greninger P, Montagut C, Lamb J, Archibald H, Raudales R, Tam A, Lee D, Rothenberg SM, Supko JG, Sordella R, Ulkus LE, Iafrate AJ, Maheswaran S, Njauw CN, Tsao H, Drew L, Hanke JH, Ma XJ, Erlander MG, Gray NS, Haber DA, Settleman J

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

Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19936-41. Epub 2007 Dec 6.

PubMed ID
18077425 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
CrizotinibALK tyrosine kinase receptorIC 50 (nM)20N/AN/ADetails
CrizotinibHepatocyte growth factor receptorIC 50 (nM)8N/AN/ADetails
ErlotinibEpidermal growth factor receptorIC 50 (nM)0.4N/AN/ADetails
ImatinibEpithelial discoidin domain-containing receptor 1IC 50 (nM)31000N/AN/ADetails
ImatinibPlatelet-derived growth factor receptor alphaEC 50 (nM)90N/AN/ADetails
SorafenibPlatelet-derived growth factor receptor betaKd (nM)41N/AN/ADetails
SorafenibReceptor-type tyrosine-protein kinase FLT3Kd (nM)20N/AN/ADetails
SorafenibSerine/threonine-protein kinase B-rafIC 50 (nM)200N/AN/ADetails
SorafenibSerine/threonine-protein kinase B-rafEC 50 (nM)3N/AN/ADetails
SorafenibVascular endothelial growth factor receptor 2Kd (nM)93N/AN/ADetails
SorafenibVascular endothelial growth factor receptor 2EC 50 (nM)500N/AN/ADetails
SorafenibVascular endothelial growth factor receptor 3Kd (nM)16N/AN/ADetails
SunitinibPlatelet-derived growth factor receptor betaKd (nM)0.2N/AN/ADetails
SunitinibReceptor-type tyrosine-protein kinase FLT3Kd (nM)0.8N/AN/ADetails
SunitinibVascular endothelial growth factor receptor 2IC 50 (nM)27N/AN/ADetails
SunitinibVascular endothelial growth factor receptor 2Kd (nM)0.2N/AN/ADetails
SunitinibVascular endothelial growth factor receptor 3Kd (nM)35N/AN/ADetails