Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy
Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy
复制标题
DOI：
10.1016/j.ccr.2007.06.005
复制
发表时间：
2007-07-01
期刊：
影响因子：
50.3
通讯作者：
Wong, Kwok-Kin
中科院分区：
文献类型：
--
作者：
Li, Danan;Shimamura, Takeshi;Wong, Kwok-Kin
EGFR T790 M突变已在肺癌患者的肿瘤中发现，最终对厄洛替尼产生耐药性。在这项研究中，我们建立了一个小鼠模型，多西环素诱导表达的突变EGFR含有L 858 R，一个厄洛替尼敏感突变，和T790 M耐药突变（EGFR TL）。EGFR TL的表达导致肺泡中具有细支气管肺泡特征的外周腺癌以及细支气管中的乳头状腺癌的发展。使用不可逆EGFR酪氨酸激酶抑制剂（TKI）HKI-272治疗仅缩小外周肿瘤，但不缩小支气管肿瘤。然而，HKI-272和雷帕霉素的组合导致两种类型的肺肿瘤的显著消退。这种联合治疗可能使EGFR T790 M突变的肺癌患者受益。
The EGFR T790M mutation has been identified in tumors from lung cancer patients that eventually develop resistance to erlotinib. In this study, we generated a mouse model with doxycycline-inducible expression of a mutant EGFR containing both L858R, an erlotinib-sensitizing mutation, and the T790M resistance mutation (EGFR TL). Expression of EGFR TL led to development of peripheral adenocarcinomas with bronchioloalveolar features in alveoli as well as papillary adenocarcinomas in bronchioles. Treatment with an irreversible EGFR tyrosine kinase inhibitor (TKI), HKI-272, shrunk only peripheral tumors but not bronchial tumors. However, the combination of HKI-272 and rapamycin resulted in significant regression of both types of lung tumors. This combination therapy may potentially benefit lung cancer patients with the EGFR T790M mutation.