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Inhibiting TRK Proteins in Clinical Cancer Therapy
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Lange AM
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Cancers (Basel)
2018[Apr]; 10
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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.
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