Development of small-molecule tropomyosin receptor kinase (TRK) inhibitors for NTRK fusion cancers

Jiang, Tingting; Wang, Guan; Liu, Yao; Feng, Lu; Wang, Meng; Liu, Jie; Chen, Yi; Ouyang, Liang

doi:10.1016/j.apsb.2020.05.004

Cited by 81 publications

(57 citation statements)

References 108 publications

(101 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For example, among brain tumors, glioblastoma, pilocytic astrocytoma, and pontine glioma can show gene fusions involving NTRK2 or NTRK3 [63,87,142,143]. A number of small-molecule acting as pan-Trk inhibitors are currently being evaluated in clinical trials [144][145][146]. A recent phase 1 and 2 clinical study examining the effects of the pan-Trk inhibitor larotrectinib in children and adults with various types of peripheral solid cancers harboring NTRK gene fusions found pronounced and durable responses regardless of patient age or tumor type [147].…”

Section: Discussionmentioning

confidence: 99%

Neurotrophin Signaling in Medulloblastoma

Thomaz

Jaeger

Brunetto

et al. 2020

Cancers

View full text Add to dashboard Cite

Neurotrophins are a family of secreted proteins that act by binding to tropomyosin receptor kinase (Trk) or p75NTR receptors to regulate nervous system development and plasticity. Increasing evidence indicates that neurotrophins and their receptors in cancer cells play a role in tumor growth and resistance to treatment. In this review, we summarize evidence indicating that neurotrophin signaling influences medulloblastoma (MB), the most common type of malignant brain cancer afflicting children. We discuss the potential of neurotrophin receptors as new therapeutic targets for the treatment of MB. Overall, activation of TrkA and TrkC types of receptors seem to promote cell death, whereas TrkB might stimulate MB growth, and TrkB inhibition displays antitumor effects. Importantly, we show analyses of the gene expression profile of neurotrophins and their receptors in MB primary tumors, which indicate, among other findings, that higher levels of NTRK1 or NTRK2 are associated with reduced overall survival (OS) of patients with SHH MB tumors.

show abstract

Section: Discussionmentioning

confidence: 99%

Neurotrophin Signaling in Medulloblastoma

Thomaz

Jaeger

Brunetto

et al. 2020

Cancers

View full text Add to dashboard Cite

show abstract

“… 36 For instance, a selenium compound, PBISe, was found to be a chemotherapeutic agent in melanoma and human HCC. 37 However, it is still necessary to explore and develop more selenium antitumor drugs with low toxicity and strong target efficacy. In the present study, we identified that SeS 2 , a compound typically found in lotion form and mainly used to treat seborrheic dermatitis and tinea versicolor, induced growth inhibition and mitochondrial apoptosis of HCC cells in vitro and in vivo in a PLAGL2‐dependent manner.…”

Section: Discussionmentioning

confidence: 99%

“…There are several reports on the anticancer activity of Se‐containing compounds, including organic, inorganic, natural, and synthetic molecules 36 . For instance, a selenium compound, PBISe, was found to be a chemotherapeutic agent in melanoma and human HCC 37 . However, it is still necessary to explore and develop more selenium antitumor drugs with low toxicity and strong target efficacy.…”

Section: Discussionmentioning

confidence: 99%

Selenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma

Yang

Huo

et al. 2021

Clinical & Translational Med

View full text Add to dashboard Cite

Background Hepatocellular carcinoma (HCC) is the third leading cause of cancer‐related deaths worldwide. Overexpression of pleomorphic adenoma gene like‐2 (PLAGL2) is associated with tumorigenesis. However, its function in HCC is unclear, and there are currently no anti‐HCC drugs that target PLAGL2. Drug repositioning may facilitate the development of PLAGL2‐targeted drug candidates. Methods The expression of PLAGL2 in HCC clinical tissue samples and HCC cell lines was analyzed by western blotting. The constructed HCC cell models were used to confirm the underlying function of PLAGL2 as a therapeutic target. Multiple in vitro and in vivo assays were conducted to determine the anti‐proliferative and apoptosis‐inducing effects of selenium sulfide (SeS 2 ), which is clinically used for the treatment of seborrheic dermatitis and tinea versicolor. Results PLAGL2 expression was higher in HCC tumor tissues than in normal adjacent tissues. Its overexpression promoted the resistance of HCC cells of mitochondrial apoptosis through the regulation of the downstream C‐MET/STAT3 signaling axis. SeS 2 exerted significant anti‐proliferative and apoptosis‐inducing effects on HCC cells in a PLAGL2‐dependent manner. Mechanistically, SeS 2 suppressed C‐MET/STAT3, AKT/mTOR, and MAPK signaling and triggered Bcl‐2/Cyto C/Caspase‐mediated intrinsic mitochondrial apoptosis both in vitro and in vivo. Conclusions Our data reveal an important role of PLAGL2 in apoptosis resistance in HCC and highlight the potential of using SeS 2 as a PLAGL2 inhibitor in patients with HCC.

show abstract

“…STARTRK-2, in particular, includes patients with salivary gland tumours harbouring a NTRK3 gene fusion, similar to that in MASC. In addition to entrectinib and larotrectinib, which are two approved therapy options, other TRKIs, such as sitravatinib, cabozantinib, belizatinib, and several more, have been evaluated in clinical trials ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

Mammary analogue secretory carcinoma of a salivary gland of the hard palate with contralateral cervical lymph node metastases: A case report

et al. 2021

View full text Add to dashboard Cite

Mammary analogue secretory carcinoma (MASC) is a rare malignant tumour of the salivary glands, with only few cases reported in the literature to date. Initial preoperative staging is crucial for all patients with an oral malignancy to visualize the tumour, detect lymph node or distant metastases and plan therapeutic interventions. In the case presented herein, radiological imaging revealed a tumour of the right hard palate with suspected positive contralateral lymph nodes. Therefore, local tumour resection comprising hemimaxillectomy and bilateral neck dissection was performed. The diagnosis of MASC was finally based on characteristic histopathological and immunohistochemical findings, such as S100 protein and mammaglobin positivity. The diagnosis of MASC may be challenging, as such findings lack specificity. To confirm the diagnosis, molecular genetic examinations may be performed to detect a highly specific ETV6-NTRK3 fusion gene. Depending on the results of these examinations, surgery, alone or combined with adjuvant radiation or chemoradiation, is the recommended approach. In summary, MASC should be treated similarly to other low-grade salivary gland tumours, such as acinic cell carcinoma, as they exhibit biological and histopathological similarities.

show abstract

Development of small-molecule tropomyosin receptor kinase (TRK) inhibitors for NTRK fusion cancers

Cited by 81 publications

References 108 publications

Neurotrophin Signaling in Medulloblastoma

Neurotrophin Signaling in Medulloblastoma

Selenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma

Mammary analogue secretory carcinoma of a salivary gland of the hard palate with contralateral cervical lymph node metastases: A case report

Contact Info

Product

Resources

About