Aberrant epidermal growth factor receptor signaling and enhanced sensitivity to EGFR inhibitors in lung cancer.
Epidermal growth factor receptor (EGFR) is occasionally amplified and/or mutated in non-small cell lung cancer (NSCLC) and can be coexpressed with other members of the HER receptor family to form functional heterodimers. We therefore investigated lung cancer cell lines for alterations in EGFR gene copy number, enhanced expression of EGFR and other HER family members, and EGFR coding sequence mutations and correlated these findings with response to treatment with the EGFR inhibitors and the kinetics of ligand-induced signaling. We show here that somatic deletions in the tyrosine kinase domain of EGFR were associated with increased EGFR gene copy number in NSCLC. Treatment with the specific EGFR tyrosine kinase inhibitors (TKI) gefitinib or erlotinib or the EGFR inhibitory antibody cetuximab induced apoptosis of HCC827, a NSCLC cell line with EGFR gene amplification and an exon 19 deletion. H1819, a NSCLC cell line that expresses high levels of EGFR, ErbB2, and ErbB3 but has wild-type EGFR, showed intermediate sensitivity to TKIs. In both cell lines, ligand-induced receptor tyrosine phosphorylation was delayed and prolonged and AKT was constitutively phosphorylated (but remained inhibitable by EGFR TKI). Thus, in addition to EGFR mutations, other factors in NSCLC cells, such as high expression of ErbB family members, may constitutively activate AKT and sensitize cells to EGFR inhibitors.
Amann
Joseph
J
Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA.
Kalyankrishna
Shailaja
S
Massion
Pierre P
PP
Ohm
Joyce E
JE
Girard
Luc
L
Shigematsu
Hisayuki
H
Peyton
Michael
M
Juroske
Denise
D
Huang
Yuhui
Y
Stuart Salmon
J
J
Kim
Young H
YH
Pollack
Jonathan R
JR
Yanagisawa
Kiyoshi
K
Gazdar
Adi
A
Minna
John D
JD
Kurie
Jonathan M
JM
Carbone
David P
DP
D000595:Amino Acid Sequence; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D017931:DNA Primers; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D017384:Sequence Deletion; D015398:Signal Transduction / Q000502:physiology*
D017931:DNA Primers; D011994:Recombinant Proteins; D066246:ErbB Receptors