Song Xiaoling, Fan Pang-Dian, Bantikassegn Amlak, Guha Udayan, Threadgill David W, Varmus Harold, Politi Katerina
Department of Pathology and Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York.
Cancer Res. 2015 Mar 15;75(6):1035-45. doi: 10.1158/0008-5472.CAN-13-1625. Epub 2015 Jan 16.
ERBB3, a member of the EGFR family of receptor tyrosine kinases, has been implicated in activation of the PI3K pathway in human lung adenocarcinomas driven by EGFR mutations. We investigated the contribution of ERBB3 to the initiation, progression, and therapeutic response of EGFR-induced lung adenocarcinomas using tetracycline- and tamoxifen-inducible transgenic mouse models. Deletion of Erbb3 at the time of induction of mutant EGFR had no effect on tumorigenesis, demonstrating that ERBB3 is not required to initiate tumorigenesis. Tumors that developed in the absence of ERBB3 remained sensitive to EGFR tyrosine kinase inhibitors and retained activation of the PI3K-AKT pathway. Interestingly, acute loss of Erbb3 suppressed further growth of established EGFR(L858R)-mediated lung tumors. Four weeks after deletion of Erbb3, the tumors exhibited phosphorylation of EGFR, of the adaptor proteins GAB1 and GAB2, and of the downstream signaling molecules AKT and ERK, suggesting that alternative signaling pathways could compensate for loss of Erbb3. Similar to our observations with mouse tumors, we found that GAB adaptor proteins play a role in ERBB3-independent activation of the PI3K pathway by mutant EGFR in EGFR-mutant human cell lines. Finally, in such cell lines, increased levels of phosphorylation of ERBB2 or MET were associated with reduced sensitivity to acute loss of ERBB3, suggesting remarkable plasticity in the signaling pathways regulated by mutant EGFR with important therapeutic implications.
ERBB3是受体酪氨酸激酶EGFR家族的成员之一，在由EGFR突变驱动的人肺腺癌中，它与PI3K途径的激活有关。我们使用四环素和他莫昔芬诱导的转基因小鼠模型，研究了ERBB3对EGFR诱导的肺腺癌的起始、进展和治疗反应的作用。在诱导突变型EGFR时删除Erbb3对肿瘤发生没有影响，这表明启动肿瘤发生不需要ERBB3。在没有ERBB3的情况下形成的肿瘤对EGFR酪氨酸激酶抑制剂仍然敏感，并保留了PI3K-AKT途径的激活。有趣的是，Erbb3的急性缺失抑制了已建立的EGFR(L858R)介导的肺肿瘤的进一步生长。删除Erbb3四周后，肿瘤表现出EGFR、衔接蛋白GAB1和GAB2以及下游信号分子AKT和ERK的磷酸化，这表明替代信号通路可以补偿Erbb3的缺失。与我们对小鼠肿瘤的观察结果相似，我们发现在EGFR突变的人类细胞系中，GAB衔接蛋白在突变型EGFR对PI3K途径的非ERBB3依赖性激活中发挥作用。最后，在这些细胞系中，ERBB2或MET磷酸化水平的升高与对ERBB3急性缺失的敏感性降低有关，这表明突变型EGFR调节的信号通路具有显著的可塑性，具有重要的治疗意义。
