Role and relevance of TrkB mutations and expression in non-small cell lung cancer.
Role and relevance of TrkB mutations and expression in non-small cell lung cancer.
复制标题
DOI：
10.1158/1078-0432.ccr-10-3034
复制
发表时间：
2011-05-01
期刊：
影响因子：
--
通讯作者：
Giaccone G
中科院分区：
文献类型：
--
作者：
Harada T;Yatabe Y;Takeshita M;Koga T;Yano T;Wang Y;Giaccone G
TrkB参与了不良的癌症结局。TrkB突变已在非小细胞肺癌中报道。在这项研究中，我们的目的是表征3个潜在的致敏TrkB突变在肺癌中的作用。我们使用NIH 3 T3细胞和Baf 3细胞表征了TrkB的三种激活环突变体（M713 I、R715 G和R734 C）在途径激活/磷酸化、迁移、锚定独立生长和对Trk抑制剂的敏感性方面。我们还对大量东亚起源的肺癌样本和细胞系中TrkB的酪氨酸激酶结构域进行了测序。在NIH 3 T3转化和迁移试验中，没有突变体具有组成型活性。与野生型TrkB相比，M713 I和R734 C突变体显示低水平的自磷酸化。虽然R715 G在脑源性神经营养因子刺激后显示出与野生型TrkB相似的自磷酸化水平，但突变体在支持Baf 3细胞的IL-3非依赖性生长方面不如野生型TrkB有能力。此外，Trk抑制剂AZD 6918抑制野生型TrkB诱导的细胞迁移和细胞生长，而与野生型TrkB相比，突变体对Trk抑制剂具有相对抗性。在78例肺癌标本和29株细胞系中，我们无法证实非同义突变的存在。野生型而非突变型TrkB增强细胞迁移和转化。我们的研究表明，TrkB突变不应用于选择用Trk抑制剂治疗的肺癌患者。野生型TrkB的高表达可能有利于Trk抑制剂的研究。
TrkB has been involved in poor cancer outcome. TrkB mutations have been reported in non-small cell lung cancer. In this study, we aimed at characterizing the role of 3 potentially sensitizing TrkB mutations previously reported in lung cancer. We characterized three activation loop mutants of TrkB (M713I, R715G and R734C) in terms of pathway activation/phosphorylation, migration, anchorage independent growth and sensitivity to a Trk inhibitor, using NIH3T3 cells and Baf3 cells. We also sequenced the tyrosine kinase domain of TrkB in a large number of lung cancer samples of East-Asian origin and cell lines. None of the mutants were constitutively active in NIH3T3 transformation and migration assays. M713I and R734C mutants showed low levels of autophosphorylation in comparison with wild-type TrkB. Although R715G showed similar level of autophosphorylation to wild-type TrkB upon brain-derived neurotrophic factor stimulation, the mutant was not as competent as wild-type TrkB in supporting IL-3 independent growth of Baf3 cells. In addition, the Trk inhibitor AZD6918 inhibited wild-type TrkB induced cell migration and cell growth, whereas the mutants were relatively resistant to the Trk inhibitor compared to wild-type TrkB. We could not confirm the presence of non-synonymous mutation in 78 lung cancer samples and 29 cell lines. Wild-type but not mutant TrkB enhances cell migration and transformation. Our study suggests that TrkB mutations should not be used for selection of patients with lung cancer treated with Trk inhibitors. High expression of wild-type TrkB might be beneficial for studies of Trk inhibitors.