TRK Inhibitors: Tissue-Agnostic Anti-Cancer Drugs

Han, Sun‐Young

doi:10.3390/ph14070632

Cited by 16 publications

(6 citation statements)

References 65 publications

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“…The activity of Trk inhibitors in the CNS is crucial because cancers that harbor NTRK fusions can present with primary or metastatic intracranial disease. The tolerability of the inhibitors was acceptable with the most frequent adverse events being anemia (10%), weight gain (14%), dyspnea, and asthenia (25%)[ 50 , 51 ]. The majority of adverse events encountered were grade 1-2.…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

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

Stravodimou¹,

Voutsadakis²

2022

WJCO

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“…When using the first‐generation TRK inhibitors, acquired resistance emerges in some patients, which is mainly caused by secondary point mutations in the tyrosine kinase domains [ 92 , 95 ]. These mutations can occur in the solvent‐front, gatekeeper residues, and the xDFG motif of the TRK enzyme.…”

Section: Targeted Trkb Inhibition In Neurogenic Tu...mentioning

confidence: 99%

Tropomyosin receptor kinase B (TrkB) signalling: targeted therapy in neurogenic tumours

Wei

Wang

et al. 2022

The Journal of Pathology CR

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Tropomyosin receptor kinase B (TrkB), a transmembrane receptor protein, has been found to play a pivotal role in neural development. This protein is encoded by the neurotrophic receptor tyrosine kinase 2 (NTRK2) gene, and its abnormal activation caused by NTRK2 overexpression or fusion can contribute to tumour initiation, progression, and resistance to therapeutics in multiple types of neurogenic tumours. Targeted therapies for this mechanism have been designed and developed in preclinical and clinical studies, including selective TrkB inhibitors and pan-TRK inhibitors. This review describes the gene structure, biological function, abnormal TrkB activation mechanism, and current-related targeted therapies in neurogenic tumours.

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“…Entrectinib is another orally available inhibitor with activity on TRKA/B/C, ROS1, and ALK (86,87) developed to reach a high concentration in the central nervous system that correlates to high intracranial activity as shown in preclinical models (88). Two phase I dose-escalation studies and a phase II basket trial STARTRK-2 (NCT02568267) supported the activity of entrectinib.…”

Section: Either Of One or Of No One: Neurotrophic Tyrosine Receptor K...mentioning

confidence: 99%

Looking Beyond the Glioblastoma Mask: Is Genomics the Right Path?

et al. 2022

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Glioblastomas are the most frequent and malignant brain tumor hallmarked by an invariably poor prognosis. They have been classically differentiated into primary isocitrate dehydrogenase 1 or 2 (IDH1 -2) wild-type (wt) glioblastoma (GBM) and secondary IDH mutant GBM, with IDH wt GBMs being commonly associated with older age and poor prognosis. Recently, genetic analyses have been integrated with epigenetic investigations, strongly implementing typing and subtyping of brain tumors, including GBMs, and leading to the new WHO 2021 classification. GBM genomic and epigenomic profile influences evolution, resistance, and therapeutic responses. However, differently from other tumors, there is a wide gap between the refined GBM profiling and the limited therapeutic opportunities. In addition, the different oncogenes and tumor suppressor genes involved in glial cell transformation, the heterogeneous nature of cancer, and the restricted access of drugs due to the blood–brain barrier have limited clinical advancements. This review will summarize the more relevant genetic alterations found in GBMs and highlight their potential role as potential therapeutic targets.

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TRK Inhibitors: Tissue-Agnostic Anti-Cancer Drugs

Cited by 16 publications

References 65 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

Tropomyosin receptor kinase B (TrkB) signalling: targeted therapy in neurogenic tumours

Looking Beyond the Glioblastoma Mask: Is Genomics the Right Path?

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