Inhibiting TRK Proteins in Clinical Cancer Therapy
Gene rearrangements resulting in the aberrant activity of tyrosine kinases have been identified as drivers of oncogenesis in a variety of cancers. The tropomyosin receptor kinase (TRK) family of tyrosine receptor kinases is emerging as an important target for cancer therapeutics. The TRK family cont...
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| Format: | Article |
| Language: | English |
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MDPI AG
2018-04-01
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| Series: | Cancers |
| Subjects: | |
| Online Access: | http://www.mdpi.com/2072-6694/10/4/105 |
| _version_ | 1797761313482473472 |
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| author | Allison M. Lange Hui-Wen Lo |
| author_facet | Allison M. Lange Hui-Wen Lo |
| author_sort | Allison M. Lange |
| collection | DOAJ |
| description | Gene rearrangements resulting in the aberrant activity of tyrosine kinases have been identified as drivers of oncogenesis in a variety of cancers. The tropomyosin receptor kinase (TRK) family of tyrosine receptor kinases is emerging as an important target for cancer therapeutics. The TRK family contains three members, TRKA, TRKB, and TRKC, and these proteins are encoded by the genes NTRK1, NTRK2, and NTRK3, respectively. To activate TRK receptors, neurotrophins bind to the extracellular region stimulating dimerization, phosphorylation, and activation of downstream signaling pathways. Major known downstream pathways include RAS/MAPK/ERK, PLCγ, and PI3K/Akt. While being rare in most cancers, TRK fusions with other proteins have been well-established as oncogenic events in specific malignancies, including glioblastoma, papillary thyroid carcinoma, and secretory breast carcinomas. TRK protein amplification as well as alternative splicing events have also been described as contributors to cancer pathogenesis. For patients harboring alterations in TRK expression or activity, TRK inhibition emerges as an important therapeutic target. To date, multiple trials testing TRK-inhibiting compounds in various cancers are underway. In this review, we will summarize the current therapeutic trials for neoplasms involving NTKR gene alterations, as well as the promises and setbacks that are associated with targeting gene fusions. |
| first_indexed | 2024-03-12T19:11:10Z |
| format | Article |
| id | doaj.art-75694c135a6e4f12b0d7cbab9a29b044 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T19:11:10Z |
| publishDate | 2018-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-75694c135a6e4f12b0d7cbab9a29b0442023-08-02T05:51:55ZengMDPI AGCancers2072-66942018-04-0110410510.3390/cancers10040105cancers10040105Inhibiting TRK Proteins in Clinical Cancer TherapyAllison M. Lange0Hui-Wen Lo1Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USADepartment of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USAGene rearrangements resulting in the aberrant activity of tyrosine kinases have been identified as drivers of oncogenesis in a variety of cancers. The tropomyosin receptor kinase (TRK) family of tyrosine receptor kinases is emerging as an important target for cancer therapeutics. The TRK family contains three members, TRKA, TRKB, and TRKC, and these proteins are encoded by the genes NTRK1, NTRK2, and NTRK3, respectively. To activate TRK receptors, neurotrophins bind to the extracellular region stimulating dimerization, phosphorylation, and activation of downstream signaling pathways. Major known downstream pathways include RAS/MAPK/ERK, PLCγ, and PI3K/Akt. While being rare in most cancers, TRK fusions with other proteins have been well-established as oncogenic events in specific malignancies, including glioblastoma, papillary thyroid carcinoma, and secretory breast carcinomas. TRK protein amplification as well as alternative splicing events have also been described as contributors to cancer pathogenesis. For patients harboring alterations in TRK expression or activity, TRK inhibition emerges as an important therapeutic target. To date, multiple trials testing TRK-inhibiting compounds in various cancers are underway. In this review, we will summarize the current therapeutic trials for neoplasms involving NTKR gene alterations, as well as the promises and setbacks that are associated with targeting gene fusions.http://www.mdpi.com/2072-6694/10/4/105NTRK gene fusionsTRKATRKBTRKCtyrosine kinase inhibitorcancerneurotrophin |
| spellingShingle | Allison M. Lange Hui-Wen Lo Inhibiting TRK Proteins in Clinical Cancer Therapy Cancers NTRK gene fusions TRKA TRKB TRKC tyrosine kinase inhibitor cancer neurotrophin |
| title | Inhibiting TRK Proteins in Clinical Cancer Therapy |
| title_full | Inhibiting TRK Proteins in Clinical Cancer Therapy |
| title_fullStr | Inhibiting TRK Proteins in Clinical Cancer Therapy |
| title_full_unstemmed | Inhibiting TRK Proteins in Clinical Cancer Therapy |
| title_short | Inhibiting TRK Proteins in Clinical Cancer Therapy |
| title_sort | inhibiting trk proteins in clinical cancer therapy |
| topic | NTRK gene fusions TRKA TRKB TRKC tyrosine kinase inhibitor cancer neurotrophin |
| url | http://www.mdpi.com/2072-6694/10/4/105 |
| work_keys_str_mv | AT allisonmlange inhibitingtrkproteinsinclinicalcancertherapy AT huiwenlo inhibitingtrkproteinsinclinicalcancertherapy |