Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling.
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.
McDermott
Ultan
U
Center for Molecular Therapeutics, Massachusetts General Hospital Cancer Center and Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA.
Sharma
Sreenath V
SV
Dowell
Lori
L
Greninger
Patricia
P
Montagut
Clara
C
Lamb
Jennifer
J
Archibald
Heidi
H
Raudales
Raul
R
Tam
Angela
A
Lee
Diana
D
Rothenberg
S Michael
SM
Supko
Jeffrey G
JG
Sordella
Raffaella
R
Ulkus
Lindsey E
LE
Iafrate
A John
AJ
Maheswaran
Shyamala
S
Njauw
Ching Ni
CN
Tsao
Hensin
H
Drew
Lisa
L
Hanke
Jeff H
JH
Ma
Xiao-Jun
XJ
Erlander
Mark G
MG
Gray
Nathanael S
NS
Haber
Daniel A
DA
Settleman
Jeffrey
J
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
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors