title: Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling.
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.
authors: Center for Molecular Therapeutics, Massachusetts General Hospital Cancer Center and Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA.
authors: Ultan
authors: U
authors: McDermott
authors: Sreenath V
authors: SV
authors: Sharma
authors: Lori
authors: L
authors: Dowell
authors: Patricia
authors: P
authors: Greninger
authors: Clara
authors: C
authors: Montagut
authors: Jennifer
authors: J
authors: Lamb
authors: Heidi
authors: H
authors: Archibald
authors: Raul
authors: R
authors: Raudales
authors: Angela
authors: A
authors: Tam
authors: Diana
authors: D
authors: Lee
authors: S Michael
authors: SM
authors: Rothenberg
authors: Jeffrey G
authors: JG
authors: Supko
authors: Raffaella
authors: R
authors: Sordella
authors: Lindsey E
authors: LE
authors: Ulkus
authors: A John
authors: AJ
authors: Iafrate
authors: Shyamala
authors: S
authors: Maheswaran
authors: Ching Ni
authors: CN
authors: Njauw
authors: Hensin
authors: H
authors: Tsao
authors: Lisa
authors: L
authors: Drew
authors: Jeff H
authors: JH
authors: Hanke
authors: Xiao-Jun
authors: XJ
authors: Ma
authors: Mark G
authors: MG
authors: Erlander
authors: Nathanael S
authors: NS
authors: Gray
authors: Daniel A
authors: DA
authors: Haber
authors: Jeffrey
authors: J
authors: Settleman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005838:Genotype; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors