Trk Receptor Expression and Inhibition in Neuroblastomas

Brodeur, Garrett M.; Minturn, Jane E.; Ho, Ruth; Simpson, Anisha M.; Iyer, Radhika; Varela, Carly R.; Light, Jennifer E.; Kolla, Venkatadri; Evans, Audrey E.

doi:10.1158/1078-0432.ccr-08-1815

Cited by 270 publications

(237 citation statements)

References 72 publications

Supporting

Mentioning

223

Contrasting

Unclassified

Order By: Relevance

“…Whereas the physiologic role of TRKA is relatively well elucidated (4), its involvement in neoplastic transformation and tumor progression was until very recently limited to identification of rearrangements in papillary thyroid carcinoma (PTC), a tumor type characterized by a relatively good prognosis and reports of activation due to presence of putative autocrine loops in neuroblastoma, prostate, pancreatic, and breast cancer (5)(6)(7)(8)(9)(10). However, chromosomal rearrangements involving the NTRK1 gene, resulting in the expression of different TRKA fusion proteins were recently reported by Vaishnavi and colleagues (11) in NSCLC, along with robust preclinical demonstration of the oncogenic potential of the predicted chimeric proteins.…”

Section: Introductionmentioning

confidence: 99%

Entrectinib, a Pan–TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

Ardini

Menichincheri

Banfi

et al. 2016

Molecular Cancer Therapeutics

262

191

View full text Add to dashboard Cite

Activated ALK and ROS1 tyrosine kinases, resulting from chromosomal rearrangements, occur in a subset of non-small cell lung cancers (NSCLC) as well as other tumor types and their oncogenic relevance as actionable targets has been demonstrated by the efficacy of selective kinase inhibitors such as crizotinib, ceritinib, and alectinib. More recently, low-frequency rearrangements of TRK kinases have been described in NSCLC, colorectal carcinoma, glioblastoma, and Spitzoid melanoma. Entrectinib, whose discovery and preclinical characterization are reported herein, is a novel, potent inhibitor of ALK, ROS1, and, importantly, of TRK family kinases, which shows promise for therapy of tumors bearing oncogenic forms of these proteins. Proliferation profiling against over 200 human tumor cell lines revealed that entrectinib is exquisitely potent in vitro against lines that are dependent on the drug's pharmacologic targets. Oral administration of entrectinib to tumor-bearing mice induced regression in relevant human xenograft tumors, including the TRKA-dependent colorectal carcinoma KM12, ROS1-driven tumors, and several ALK-dependent models of different tissue origins, including a model of brain-localized lung cancer metastasis. Entrectinib is currently showing great promise in phase I/II clinical trials, including the first documented objective responses to a TRK inhibitor in colorectal carcinoma and in NSCLC. The drug is, thus, potentially suited to the therapy of several molecularly defined cancer settings, especially that of TRK-dependent tumors, for which no approved drugs are currently available.

show abstract

Section: Introductionmentioning

confidence: 99%

Entrectinib, a Pan–TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

Ardini

Menichincheri

Banfi

et al. 2016

Molecular Cancer Therapeutics

262

191

View full text Add to dashboard Cite

show abstract

“…Numerous studies have shown that high expression of TrkA in neuroblastoma tissue is associated with improved clinical characteristics in patients and lower MYCN gene amplification, while patients in the advanced stages of neuroblastoma usually exhibit lower expression levels of TrkA and the tumors cannot be treated with NGF to inhibit differentiation (24)(25)(26). The NGF/TrkA signaling pathway is important in promoting neuroblastoma differentiation and natural regression (13,27,28). High expression of TrkA protein in neuroblastoma cells is associated with differentiation and regression (28)(29)(30), while lower TrkA expression is associated with increased invasiveness.…”

Section: A B C Dmentioning

confidence: 99%

“…Ras/MAPK and AKT are activated downstream of these signaling pathways. Ras sequentially activates a series of kinases, including RAF1, mitogen-activated protein kinase kinase, mitogen-activated protein kinase (MAPK) and ribosomal S6 kinase (RSK) (13). MAPK and RSK translocate to the nucleus to initiate the activation of transcription factors that regulate NGF-inducible genes, leading to survival and neuronal differentiation.…”

Section: A B C Dmentioning

confidence: 99%

“…However, neuroblastoma with TrkB expression results in a poor prognosis due to amplification of the MYCN gene. TrkB ligands from neuroblastoma, via autocrine or paracrine survival pathways, may enhance the viability, drug resistance and angiogenesis of TrkB-expressing tumors (13). To the best of our knowledge, no studies have confirmed the association between the miRNA17-92 cluster and the TrK family.…”

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

Downregulation of TrkA protein expression by miRNA-92a promotes the proliferation and migration of human neuroblastoma cells

Liao

Zhang

Chen

et al. 2014

Molecular Medicine Reports

View full text Add to dashboard Cite

Abstract. The aims of this study were to investigate the regulation of TrkA protein by micro (mi)RNA-92a and its effect on the proliferation and migration of human neuroblastoma cells. The BE(2)-M17 human neuroblastoma cell line was cultured and transfected with either miRNA-92a mimics or miRNA-92a inhibitors. The expression levels of miRNA-92a and TrkA mRNA were detected by quantitative polymerase chain reaction prior and subsequent to transfection. TrkA protein was quantitatively detected by flow cytometry. The proliferation and migration of neuroblastoma cells were examined in vitro by Cell Counting Kit-8 and Transwell assays. Transfection of BE(2)-M17 cells with miRNA-92a mimics produced significantly higher expression levels of miRNA-92a compared with those in the same cells transfected with negative controls (NCs). Increased proliferation and migration of the cells was also observed. Transfection of BE(2)-M17 cells with miRNA-92a inhibitors resulted in significantly lower expression levels of miRNA-92a when compared with those of the same cells transfected with NCs (P<0.01). This reduction in the miRNA-92a expression levels was accompanied by reduced proliferation and migration of the cells. The expression levels of TrkA mRNA and protein after 24 h transfection with the miRNA-92a mimics were significantly reduced when compared with the control (P<0.01). However, the expression levels of TrkA were significantly higher (P<0.01) after 48 h transfection with miRNA-92a inhibitors when compared with the control. In conclusion, miRNA-92a promoted the proliferation and migration of human neuroblastoma cells through downregulation of TrkA, which suggested that miRNA-92a may be a potential target for human neuroblastoma treatment in the future.

show abstract

“…The NTRK family plays a role in the development of the nervous system with the modulation of growth, proliferation, repair, maintenance and apoptosis. 1,2 However, NTRK fusions are also present in solid tumors as oncogenic fusions responsible for growth of cancer cells, proliferation, and survival; the presence of these three oncogenes is associate with poor survival in lung cancers. 3,4 NTRK1 oncogenic fusions have been detected by fluorescent in situ hybridization (FISH) or next generation sequencing in about 3% of NSCLC, while NTRK2 and NTRK3 fusions in about 1% of NSCLC of all types.…”

mentioning

confidence: 99%

New targets bring hope in squamous cell lung cancer: neurotrophic tyrosine kinase gene fusions

Rolfo

Raez

2017

Laboratory Investigation

View full text Add to dashboard Cite

Neurotrophic tyrosine kinase genes encode for the Trk-family proteins TrkA, TrkB, and TrkC, which have an important role in the development of the nervous system; however, they have been identified as oncogenic fusions in solid tumors (NTK-1, NTRK-2, and NTRK-3) and are associated with poor survival in lung cancer. These three new fusions can be detected by fluorescent in situ hybridization or next-generation sequencing in less than 5% of the lung tumors. There are several ongoing clinical trials of NTRK oncogenes in lung cancer and other tumors. The agents entrectinib (RXDX-101), a multi-kinase small molecule inhibitor that selectively inhibits NTRK1, NTRK2, and NTRK3, ROS1 and ALK, and LOXO-101, an ATP-competitive pan-NTRK inhibitor, have shown responses in patients with lung cancer with an acceptable toxicity profile. Although these oncogenic fusions are not very prevalent, the high prevalence of lung cancer makes these findings very relevant and suggests the feasibility of these oncogenes as targets in lung cancer. New data from Ozono and collaborators presented in this issue suggest that BDNF/TrkB signal promotes proliferating migratory and invasive phenotypes and cellular plasticity in squamous cell carcinoma (SCC) of the lung but that it also represents a druggable target that may bring hope to squamous lung cancer patients.

show abstract

Trk Receptor Expression and Inhibition in Neuroblastomas

Cited by 270 publications

References 72 publications

Entrectinib, a Pan–TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

Entrectinib, a Pan–TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

Downregulation of TrkA protein expression by miRNA-92a promotes the proliferation and migration of human neuroblastoma cells

New targets bring hope in squamous cell lung cancer: neurotrophic tyrosine kinase gene fusions

Contact Info

Product

Resources

About