TY - JOUR
T1 - Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors
AU - Ji, Hongbin
AU - Zhao, Xiaojun
AU - Yuza, Yuki
AU - Shimamura, Takeshi
AU - Li, Danan
AU - Protopopov, Alexei
AU - Jung, Boonim L.
AU - McNamara, Kate
AU - Xia, Huili
AU - Glatt, Karen A.
AU - Thomas, Roman K.
AU - Sasaki, Hidefumi
AU - Horner, James W.
AU - Eck, Michael
AU - Mitchell, Albert
AU - Sun, Yangping
AU - Al-Hashem, Ruqayyah
AU - Bronson, Roderick T.
AU - Rabindran, Sridhar K.
AU - Discafani, Carolyn M.
AU - Maher, Elizabeth
AU - Shapiro, Geoffrey I.
AU - Meyerson, Matthew
AU - Wong, Kwok Kin
PY - 2006/5/16
Y1 - 2006/5/16
N2 - The tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) have shown anti-tumor activity in the treatment of non-small cell lung cancer (NSCLC). Dramatic and durable responses have occurred in NSCLC tumors with mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). In contrast, these inhibitors have shown limited efficacy in glioblastoma, where a distinct EGFR mutation, the variant III (vIII) in-frame deletion of exons 2-7, is commonly found. In this study, we determined that EGFRvIII mutation was present in 5% (3/56) of analyzed human lung squamous cell carcinoma (SCC) but was not present in human lung adenocarcinoma (0/123). We analyzed the role of the EGFRvIII mutation in lung tumorigenesis and its response to tyrosine kinase inhibition. Tissue-specific expression of EGFRvIII in the murine lung led to the development of NSCLC. Most importantly, these lung tumors depend on EGFRvIII expression for maintenance. Treatment with an irreversible EGFR inhibitor, HKI-272, dramatically reduced the size of these EGFRvIII-driven murine tumors in 1 week. Similarly, Ba/F3 cells transformed with the EGFRvIII mutant were relatively resistant to gefitinib and erlotinib in vitro but proved sensitive to HKI-272. These findings suggest a therapeutic strategy for cancers harboring the EGFRvIII mutation.
AB - The tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) have shown anti-tumor activity in the treatment of non-small cell lung cancer (NSCLC). Dramatic and durable responses have occurred in NSCLC tumors with mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). In contrast, these inhibitors have shown limited efficacy in glioblastoma, where a distinct EGFR mutation, the variant III (vIII) in-frame deletion of exons 2-7, is commonly found. In this study, we determined that EGFRvIII mutation was present in 5% (3/56) of analyzed human lung squamous cell carcinoma (SCC) but was not present in human lung adenocarcinoma (0/123). We analyzed the role of the EGFRvIII mutation in lung tumorigenesis and its response to tyrosine kinase inhibition. Tissue-specific expression of EGFRvIII in the murine lung led to the development of NSCLC. Most importantly, these lung tumors depend on EGFRvIII expression for maintenance. Treatment with an irreversible EGFR inhibitor, HKI-272, dramatically reduced the size of these EGFRvIII-driven murine tumors in 1 week. Similarly, Ba/F3 cells transformed with the EGFRvIII mutant were relatively resistant to gefitinib and erlotinib in vitro but proved sensitive to HKI-272. These findings suggest a therapeutic strategy for cancers harboring the EGFRvIII mutation.
KW - Irreversible inhibitor
KW - Lung cancer
KW - Lung squamous cell carcinoma
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U2 - 10.1073/pnas.0510284103
DO - 10.1073/pnas.0510284103
M3 - Article
C2 - 16672372
AN - SCOPUS:33646716077
SN - 0027-8424
VL - 103
SP - 7817
EP - 7822
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 20
ER -