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Published on: July 21, 2018
Role and relevance of TrkB mutations and expression in non-small cell lung cancer
Taishi Harada1, Yasushi Yatabe, Masafumi Takeshita
1Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
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.
Insights
TrkB mutations do not enhance lung cancer cell migration or transformation. These mutations also confer resistance to Trk inhibitors, suggesting they are not suitable for patient selection in targeted therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Tropomyosin receptor kinase B (TrkB) signaling is implicated in cancer progression.
- Specific TrkB mutations have been identified in non-small cell lung cancer (NSCLC).
- Understanding the functional impact of these mutations is crucial for targeted therapy development.
Purpose of the Study:
- To characterize the functional role of three specific TrkB mutations (M713I, R715G, R734C) in lung cancer.
- To assess the impact of these mutations on TrkB pathway activation, cell migration, and anchorage-independent growth.
- To evaluate the sensitivity of mutant TrkB to a Trk inhibitor (AZD6918).
Main Methods:
- Activation loop mutants of TrkB (M713I, R715G, R734C) were generated and characterized in NIH3T3 and Baf3 cell lines.
- Assays included pathway activation/phosphorylation, cell migration, and anchorage-independent growth.
- Sensitivity to the Trk inhibitor AZD6918 was assessed. Tyrosine kinase domain sequencing was performed on lung cancer samples and cell lines.
Main Results:
- None of the TrkB mutants exhibited constitutive activity or transformation potential.
- Mutants M713I and R734C showed reduced autophosphorylation; R715G displayed impaired interleukin-3-independent growth.
- Mutant TrkB proteins were relatively resistant to the Trk inhibitor AZD6918 compared to wild-type TrkB. No nonsynonymous mutations were found in tested lung cancer samples.
Conclusions:
- Wild-type TrkB, not mutant forms, promotes cell migration and transformation.
- TrkB mutations are unlikely to be predictive biomarkers for selecting lung cancer patients for Trk inhibitor therapy.
- High expression of wild-type TrkB may be a relevant factor for Trk inhibitor efficacy.
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