Ji Hongbin, Li Danan, Chen Liang, Shimamura Takeshi, Kobayashi Susumu, McNamara Kate, Mahmood Umar, Mitchell Albert, Sun Yangping, Al-Hashem Ruqayyah, Chirieac Lucian R, Padera Robert, Bronson Roderick T, Kim William, Jänne Pasi A, Shapiro Geoffrey I, Tenen Daniel, Johnson Bruce E, Weissleder Ralph, Sharpless Norman E, Wong Kwok-Kin
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Cancer Cell. 2006 Jun;9(6):485-95. doi: 10.1016/j.ccr.2006.04.022. Epub 2006 May 25.
To understand the role of human epidermal growth factor receptor (hEGFR) kinase domain mutations in lung tumorigenesis and response to EGFR-targeted therapies, we generated bitransgenic mice with inducible expression in type II pneumocytes of two common hEGFR mutants seen in human lung cancer. Both bitransgenic lines developed lung adenocarcinoma after sustained hEGFR mutant expression, confirming their oncogenic potential. Maintenance of these lung tumors was dependent on continued expression of the EGFR mutants. Treatment with small molecule inhibitors (erlotinib or HKI-272) as well as prolonged treatment with a humanized anti-hEGFR antibody (cetuximab) led to dramatic tumor regression. These data suggest that persistent EGFR signaling is required for tumor maintenance in human lung adenocarcinomas expressing EGFR mutants.
为了解人表皮生长因子受体（hEGFR）激酶结构域突变在肺肿瘤发生及对EGFR靶向治疗反应中的作用，我们构建了双转基因小鼠，可在II型肺细胞中诱导表达在人类肺癌中常见的两种hEGFR突变体。在持续表达hEGFR突变体后，两个双转基因品系均发生了肺腺癌，证实了它们的致癌潜力。这些肺肿瘤的维持依赖于EGFR突变体的持续表达。用小分子抑制剂（厄洛替尼或HKI-272）治疗以及用人源化抗hEGFR抗体（西妥昔单抗）长期治疗均导致肿瘤显著消退。这些数据表明，在表达EGFR突变体的人肺腺癌中，持续的EGFR信号传导是肿瘤维持所必需的。
