Abstract 1120: Role and relevance of TrkB mutations and expression in non-small cell lung cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Purpose: TrkB oncogene 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 mutations previously reported in TrkB 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 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 upon BDNF 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 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. Conclusions: Wild-type TrkB but not its activation loop mutations 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. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1120. doi:10.1158/1538-7445.AM2011-1120