High-throughput lung cancer cell line screening for genotype-correlated sensitivity to an EGFR kinase inhibitor.
Human cancer cell lines that can be propagated and manipulated in culture have proven to be excellent models for studying many aspects of gene function in cancer. In addition, they can provide a powerful system for assessing the molecular determinants of sensitivity to anticancer drugs. They have also been used in recent studies to identify genomic alterations and gene expression patterns that provide important insights into the genetic features that distinguish the properties of tumor cells associated with similar histologies. We have established a large repository of human tumor cell lines (>1000) corresponding to a wide variety of tumor types, and we have developed a methodology for profiling the collection for sensitivity to putative anticancer compounds. The rationale for examining tumor cell lines on this relatively large scale reflects accumulating evidence indicating that there is substantial genetic heterogeneity among human tumor cells-even those derived from tumors of similar histologies. Thus, to develop an accurate picture of the molecular determinants of tumorigenesis and response to therapy, it is essential to study the nature of such heterogeneity in a relatively large sample set. Here, we describe the methodologies used to conduct such screens and we describe a "proof-of-concept" screen using the EGFR kinase inhibitor, erlotinib (Tarceva), with a panel of lung cancer lines to demonstrate a correlation between EGFR mutations and drug sensitivity.
McDermott
Ultan
U
Center for Molecular Therapeutics, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts, USA.
Sharma
Sreenath V
SV
Settleman
Jeffrey
J
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D011799:Quinazolines / Q000494:pharmacology*
D000970:Antineoplastic Agents; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors