Role and Relevance of TrkB Mutations and Expression in Non-Small Cell Lung Cancer

Purpose: 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 three potentially sensitizing TrkB mutations previously reported in lung cancer. Experimental Design: 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. Results: 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 on brain-derived neurotrophic factor stimulation, the mutant was not as competent as wild-type TrkB in supporting interleukin-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 with wild-type TrkB. We could not confirm the presence of nonsynonymous mutation in 78 lung cancer samples and 29 cell lines. Conclusions: 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. Clin Cancer Res; 17(9); 2638-45. (C)2011 AACR.