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Ref Type

Journal Article

PMID

(21242122)

Authors

Harada T, Yatabe Y, Takeshita M, Koga T, Yano T, Wang Y, Giaccone G

Title

Role and relevance of TrkB mutations and expression in non-small cell lung cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	17	9	2011 May 01	2638-45	Clin Cancer Res

URL

Abstract Text

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.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 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.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.

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
NTRK2	NCBI	DEE58\|EIEE58\|GP145-TrkB\|OBHD\|trk-B\|TRKB		NTRK2, neurotrophic receptor tyrosine kinase 2, is membrane receptor tyrosine kinase that binds neurotrophins, initiating signaling cascades that lead to cell growth and differentiation (PMID: 17008023). Inappropriately regulated NTRK2 may be involved in initiation and metastasis of some cancers (PMID: 17008023) and NTRK2 fusions, with multiple gene partners, have been commonly observed in solid tumors (PMID: 32319699), including glioma (PMID: 28512244, PMID: 24705251), while NTRK2 missense mutations may confer resistance to TRK inhibition (PMID: 21242122).	Unknown

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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
NTRK2	M713I	missense	loss of function	NTRK2 M713I (corresponds to M697I in the canonical isoform) lies within the protein kinase domain of the Ntrk2 protein (UniProt.org). M713I results in loss of Ntrk2 autophosphorylation, decreased phosphorylation of Ntrk2, Akt and Erk upon growth factor stimulation, is not transforming in cell culture, and is associated with resistance to a Trk inhibitor (PMID: 21242122).	Y
NTRK2	R715G	missense	loss of function	NTRK2 R715G (corresponds to R699G in the canonical isoform) lies within the protein kinase domain of the Ntrk2 protein (UniProt.org). R715G demonstrates decreased autophosphorylation and phosphorylation of Ntrk2, Akt and Erk upon growth factor stimulation, does not support anchorage independent growth, and is associated with resistance to a Trk inhibitor in culture (PMID: 21242122).	Y
NTRK2	R734C	missense	loss of function	NTRK2 R734C (corresponds to R718C in the canonical isoform) lies within the protein kinase domain of the Ntrk2 protein (UniProt.org). R734C results in loss of Ntrk2 autophosphorylation, decreased phosphorylation of Ntrk2, Akt and Erk upon growth factor stimulation, is not transforming, and is associated with resistance to a Trk inhibitor in cell culture (PMID: 21242122).	Y

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
NTRK2 M713I	Advanced Solid Tumor	resistant	AZD6918	Preclinical	Actionable	In a preclinical study, a transformed cell line expressing NTRK2 M713I was resistant to inhibition of Ntrk2 autophosphorylation and BDNF-induced cell proliferation by AZD6918 treatment in culture (PMID: 21242122).	21242122
NTRK2 R715G	Advanced Solid Tumor	resistant	AZD6918	Preclinical	Actionable	In a preclinical study, a transformed cell line expressing NTRK2 R715G was resistant to inhibition of Ntrk2 autophosphorylation and BDNF-induced cell proliferation by AZD6918 treatment in culture (PMID: 21242122).	21242122
NTRK2 R734C	Advanced Solid Tumor	resistant	AZD6918	Preclinical	Actionable	In a preclinical study, a transformed cell line expressing NTRK2 R734C was resistant to inhibition of Ntrk2 autophosphorylation and BDNF-induced cell proliferation by AZD6918 treatment in culture (PMID: 21242122).	21242122
NTRK2 wild-type	Advanced Solid Tumor	sensitive	AZD6918	Preclinical	Actionable	In a preclinical study, AZD6918 treatment inhibited Ntrk2 autophosphorylation and BDNF-induced cell proliferation of transformed cell lines expressing wild-type Ntrk2 in culture (PMID: 21242122).	21242122

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