The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer

Griffin, Nathan; Marsland, Mark; Roselli, Séverine; Oldmeadow, Christopher; Attia, John; Walker, Marjorie M.; Hondermarck, Hubert; Faulkner, Sam

doi:10.3390/biom10091329

Cited by 11 publications

(8 citation statements)

References 43 publications

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“…Although amplification of the NTRK1 gene does not always lead to mRNA over-expression, TrkA protein is expressed in many breast cancers and thus can be a therapeutic target. In contrast to our results, another study that examined expression of TrkA at the protein level suggested that the receptor is more often expressed in HER2 positive cancers compared to luminal and basal carcinomas[ 64 ]. This study also confirmed discrepancies between gene dosage and protein expression.…”

Section: Discussioncontrasting

confidence: 99%

Neurotrophic receptor tyrosine kinase family members in secretory and non-secretory breast carcinomas

Stravodimou¹,

Voutsadakis²

2022

WJCO

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BACKGROUND Breast cancer is the most common female cancer and a major cause of morbidity and mortality. Progress in breast cancer therapeutics has been attained with the introduction of targeted therapies for specific sub-sets. However, other subsets lack targeted interventions and thus there is persisting need for identification and characterization of molecular targets in order to advance breast cancer therapeutics. AIM To analyze the role of lesions in neurotrophic receptor tyrosine kinase (NTRK) genes in breast cancers. METHODS Analysis of publicly available genomic breast cancer datasets was performed for identification and characterization of cases with fusions and other molecular abnormalities involving NTRK1 , NTRK2 and NTRK3 genes. RESULTS NTRK fusions are present in a small number of breast cancers at the extensive GENIE project data set which contains more than 10000 breast cancers. These cases are not identified as secretory in the database, suggesting that the histologic characterization is not always evident. In the breast cancer The Cancer Genome Atlas (TCGA) cohort the more common molecular lesion in NTRK genes is amplification of NTRK1 observed in 7.9% of breast cancers. CONCLUSION Neurotrophin receptors molecular lesions other than fusions are observed more often than fusions. However, currently available NTRK inhibitors are effective mainly for fusion lesions. Amplifications of NTRK1 , being more frequent in breast cancers, could be a viable therapeutic target if inhibitors efficacious for them become available.

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Section: Discussioncontrasting

confidence: 99%

Neurotrophic receptor tyrosine kinase family members in secretory and non-secretory breast carcinomas

Stravodimou¹,

Voutsadakis²

2022

WJCO

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“…Since we demonstrated that blocking NGF action, and specifically TRKA signaling, impairs OPC survival and differentiation, we hypothesized that also the protection from OGD-induced cell death may occur through this receptor. In fact, TRKA activation by NGF protects cultured neurons from glucose levels fluctuation by activating the AKT pathway ( Yan et al, 2020 ), a signal transduction path which is activated by NGF in different cell types ( Geetha et al, 2013 ; Griffin et al, 2020 ). In these contexts, NGF seems to exert its action, by TRKA interaction, increasing the presence of the phosphorylated form of AKT in the nucleus ( Xuan Nguyen et al, 2006 ).…”

Section: Discussionmentioning

confidence: 99%

Nerve growth factor promotes differentiation and protects the oligodendrocyte precursor cells from in vitro hypoxia/ischemia

Baldassarro

Cescatti²,

Rocco³

et al. 2023

Front. Neurosci.

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IntroductionNerve growth factor (NGF) is a pleiotropic molecule acting on different cell types in physiological and pathological conditions. However, the effect of NGF on the survival, differentiation and maturation of oligodendrocyte precursor cells (OPCs) and oligodendrocytes (OLs), the cells responsible for myelin formation, turnover, and repair in the central nervous system (CNS), is still poorly understood and heavily debated.MethodsHere we used mixed neural stem cell (NSC)-derived OPC/astrocyte cultures to clarify the role of NGF throughout the entire process of OL differentiation and investigate its putative role in OPC protection under pathological conditions.ResultsWe first showed that the gene expression of all the neurotrophin receptors (TrkA, TrkB, TrkC, and p75NTR) dynamically changes during the differentiation. However, only TrkA and p75NTR expression depends on T3-differentiation induction, as Ngf gene expression induction and protein secretion in the culture medium. Moreover, in the mixed culture, astrocytes are the main producer of NGF protein, and OPCs express both TrkA and p75NTR. NGF treatment increases the percentage of mature OLs, while NGF blocking by neutralizing antibody and TRKA antagonist impairs OPC differentiation. Moreover, both NGF exposure and astrocyte-conditioned medium protect OPCs exposed to oxygenglucose deprivation (OGD) from cell death and NGF induces an increase of AKT/pAKT levels in OPCs nuclei by TRKA activation.DiscussionThis study demonstrated that NGF is implicated in OPC differentiation, maturation, and protection in the presence of metabolic challenges, also suggesting implications for the treatment of demyelinating lesions and diseases.

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“…In vitro experiments have shown that TrkA overexpression enhances BC cell growth and invasion by activating Erk1/2 and PI3K-AKT-mediated signaling pathways ( 54 ). Functional experiments have demonstrated that TrkA inhibitor reduces cell viability by decreasing phosphorylated TrkA and downstream AKT, providing therapy for HER2-positive BC ( 55 ). For those drugs that have not yet been applied in the clinic, our study provides some theoretical basis for their development.…”

Section: Discussionmentioning

confidence: 99%

Identification of a basement membrane-related gene signature for predicting prognosis and estimating the tumor immune microenvironment in breast cancer

et al. 2022

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IntroductionBreast cancer (BC) is the most common malignancy in the world and has a high cancer-related mortality rate. Basement membranes (BMs) guide cell polarity, differentiation, migration and survival, and their functions are closely related to tumor diseases. However, few studies have focused on the association of basement membrane-related genes (BMRGs) with BC. This study aimed to explore the prognostic features of BMRGs in BC and provide new directions for the prevention and treatment of BC.MethodsWe collected transcriptomic and clinical data of BC patients from TCGA and GEO datasets and constructed a predictive signature for BMRGs by using univariate, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis. The reliability of the model was further evaluated and validated by Kaplan-Meier survival curves and receiver operating characteristic curves (ROC). Column line plots and corresponding calibration curves were constructed. Possible biological pathways were investigated by enrichment analysis. Afterward, we assessed the mutation status by tumor mutational burden (TMB) analysis and compared different subtypes using cluster analysis. Finally, we examined drug treatment sensitivity and immunological correlation to lay the groundwork for more in-depth studies in this area.ResultsThe prognostic risk model consisted of 7 genes (FBLN5, ITGB2, LAMC3, MMP1, EVA1B, SDC1, UNC5A). After validation, we found that the model was highly reliable and could accurately predict the prognosis of BC patients. Cluster analysis showed that patients with cluster 1 had more sensitive drugs and had better chances of better clinical outcomes. In addition, TMB, immune checkpoint, immune status, and semi-inhibitory concentrations were significantly different between high and low-risk groups, with lower-risk patients having the better anti-cancer ability.DiscussionThe basement membrane-related gene signature that we established can be applied as an independent prognostic factor for BC and can provide a reference for individualized treatment of BC patients.

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The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer

Cited by 11 publications

References 43 publications

Neurotrophic receptor tyrosine kinase family members in secretory and non-secretory breast carcinomas

Neurotrophic receptor tyrosine kinase family members in secretory and non-secretory breast carcinomas

Nerve growth factor promotes differentiation and protects the oligodendrocyte precursor cells from in vitro hypoxia/ischemia

Identification of a basement membrane-related gene signature for predicting prognosis and estimating the tumor immune microenvironment in breast cancer

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