Abstract for presentation at 11th International Congress of Human Genetics

At GlaxoSmithKline, we have created a robust pipeline of targeted cancer drugs, exemplified by lapatinib (Tykerb^TM), a dual ErbB1/ErbB2 tyrosine kinase inhibitor showing promise for several types of cancer. A key element of this pipeline is the integrated use of multiple genetics and genomics techniques. RNAi gene knockdown is being employed not only to validate targets, but also to dissect drug mechanism of action and develop hypotheses for combination therapies. Gene expression profiling, gene copy number analysis, DNA sequencing, and SNP genotyping are being used to characterize cancer models and to identify biomarkers of drug response, resistance, and safety. Such genetic and genomic biomarker studies are being conducted both preclinically and at all stages of clinical research. These and other approaches are integrated into a unified strategy and supported by an infrastructure which includes platform technologies, bioinformatics, a tumor specimen repository, and cross-disciplinary teams. Our strategy will be outlined and illustrated by our development of lapatinib. Several pharmacogenetic approaches have shown that, unlike the anti-cancer drug gefitinib (Iressa^TM), mutations in ERBB1 do not appear to correlate with lapatinib response, whereas amplification of ERBB2 does. Gene expression profiling has revealed that upregulation of estrogen receptor (ER) signaling by lapatinib contributes to the development of acquired resistance in a preclinical model, and RNAi studies demonstrated that knockdown of ER abrogates this lapatinib resistance. These findings support the hypothesis that combining lapatinib with certain anti-estrogen therapies may prevent the onset of acquired resistance to lapatinib and merits testing in the clinic. In addition, challenges we’ve faced, such as the need for better genetic characterization of preclinical models and collection of patient specimens, will be discussed.