An epidermal growth factor receptor intron 1 polymorphism mediates response to epidermal growth factor receptor inhibitors.
This study tested the hypothesis that the number of CA single sequence repeat (CA-SSR) in the intron 1 of the epidermal growth factor receptor (egfr) gene, which affects transcription efficiency of the gene, is associated with the response to EGFR inhibitors. To this end, we determined the number of CA dinucleotides in the intron 1 of the egfr gene in a panel of 12 head and neck cancer cell lines that lack egfr gene amplification and measured the expression of EGFR (mRNA and protein), as well as response to EGFR inhibition. Cells with lower number of CA dinucleotides in the CA-SSR had higher expression of the EGFR gene and protein and were more sensitive to the inhibitory effects of erlotinib, a small molecule inhibitor of the EGFR tyrosine-kinase. Phenotypic modification by silencing EGFR mRNA expression in a susceptible cell line induced resistance to the drug. The number of CA dinucleotide was equivalent in genomic and tumor DNA obtained from 30 patients with head and neck cancer. In a clinical study in colorectal cancer, subjects with lower number of CA dinucleotide frequently developed skin toxicity, a feature that is related to the antitumor activity of this class of drugs. These results suggest that polymorphic variations in the intron 1 of the egfr gene is associated with response to EGFR inhibitors and may provide an explanation as to why the development of skin toxicity is associated with a favorable outcome in patients treated with these agents.
Amador
Maria L
ML
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Oppenheimer
Darin
D
Perea
Sofia
S
Maitra
Anirban
A
Cusatis
George
G
Cusati
George
G
Iacobuzio-Donahue
Christi
C
Baker
Sharyn D
SD
Ashfaq
Raheela
R
Takimoto
Chris
C
Forastiere
Arlene
A
Hidalgo
Manuel
M
D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D018900:Dinucleotide Repeats; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D020868:Gene Silencing; D018773:Genes, erbB-1 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007438:Introns; D011110:Polymorphism, Genetic; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011799:Quinazolines / Q000009:adverse effects / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012867:Skin / Q000187:drug effects
D004273:DNA, Neoplasm; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib