Epidermal growth factor receptor mutations and susceptibility to targeted therapy in lung cancer.
According to 2002 estimates, 1.35 million people were diagnosed with and 1.18 million died of lung cancer worldwide. Recently, a new class of medications targeting signal transduction pathways has come into focus in the treatment of various malignancies. In lung cancer, the molecules gefitinib and erlotinib which target the intracellular kinase domain of the epidermal growth factor receptor (EGFR), cause significant tumour responses and, in the case of erlotinib, a survival benefit in patients with previously treated cancers. Responses were most pronounced in female non-smokers with adenocarcinoma histology. These patients were found more likely to harbour mutations of the receptor kinase domain, including in-frame deletions in exon 19 (such as deletions of codons 746-750) and point deletions in exon 21 (such as L858R). Other EGFR kinase domain mutations have been found to confer resistance (T790M) or differential susceptibility to erlotinib and gefitinib (E884K). Gene amplification of EGFR also may predict sensitivity, although the mechanism by which this occurs is unclear, because level of expression detected by immunohistochemistry has not been correlated with increased sensitivity. Phenotypic and genotypic epithelial to mesenchymal transition may be an indicator of resistance to EGFR kinase inhibitors. In this article, we review efforts that have been undertaken to identify genomic determinants of drug susceptibility to EGFR tyrosine kinase inhibitors, with particular focus on the role of gene mutations.
Ahmed
Syed M
SM
Section of Hematology/Oncology, Department of Medicine, The University of Chicago Medical Center, The Pritzker School of Medicine, Chicago, IL 60637, USA.
Salgia
Ravi
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib