Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors

被引:203
作者
Ji, Hongbin
Zhao, Xiaojun
Yuza, Yuki
Shimamura, Takeshi
Li, Danan
Protopopov, Alexei
Jung, Boonim L.
McNamara, Kate
Xia, Huili
Glatt, Karen A.
Thomas, Roman K.
Sasaki, Hidefumi
Horner, James W.
Eck, Michael
Mitchell, Albert
Sun, Yangping
Al-Hashem, Ruqayyah
Bronson, Roderick T.
Rabindran, Sriclhar K.
Discafani, Carolyn M.
Maher, Elizabeth
Shapiro, Geoffrey I.
Meyerson, Matthew [1 ]
Wong, Kwok-Kin
机构
[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
[2] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA
[3] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA
[4] Nagoya City Univ, Sch Med, Dept Surg, Nagoya, Aichi 4678601, Japan
[5] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA
[6] Wyeth Ayerst Res, Oncol Res, Pearl River, NY 10965 USA
[7] Harvard Univ, Broad Inst, Cambridge, MA 02139 USA
[8] MIT, Cambridge, MA 02139 USA
关键词
irreversible inhibitor; lung cancer; lung squamous cell carcinoma;
D O I
10.1073/pnas.0510284103
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:7817 / 7822
页数:6
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