Abstract
Tropomyosin receptor kinase (TK) is encoded by the neurotrophic tyrosine receptor kinase genes (NTRK) 1, 2, and 3, whose activation plays an important role in cell cycle proliferation and survival. Fusions of one of these genes can lead to constitutive activation of TRK, which can potentially be oncogenic. NTRK fusions are commonly present in rare histologic tumor types. Among sarcomas, infantile fibrosarcoma shows NTRK fusion in more than 90% of the cases. Many other sarcoma types are also investigated for NTRK fusions. These fusions are druggable alteration of the agnostic type, meaning that all NTRK fused tumors can be treated with NTRK-inhibitors regardless of tumor type or tissue of origin. TRK-inhibitors have shown good response rates, with durable effects and limited side effects. Resistance to therapy will eventually occur in some cases, wherefore the next-generation TRK-inhibitors are introduced. The diagnosis of NTRK fused tumors, among them sarcomas, remains an issue, as many algorithms but no guidelines exist to date. Given the importance of this diagnosis, in this paper we aim to (1) analyze the histopathological features of sarcomas that correlate more often with NTRK fusions, (2) give an overview of the TRK-inhibitors and the problems that arise from resistance to the therapy, and (3) discuss the diagnostic algorithms of NTRK fused tumors with emphasis on sarcomas.
Highlights
The Role of neurotrophic tyrosine receptor kinase genes (NTRK) in OncogenesisTropomyosin receptor kinase (TRK) is a member of the tyrosine kinase family, predominantly expressed in neuronal tissue [1]
While reviewing the literature we found a range of case studies describing NTRK fused sarcomas
Scheme 1 suggests a diagnostic algorithm for detection of NTRK fusions in sarcomas, according to the data presented in this review
Summary
Tropomyosin receptor kinase (TRK) is a member of the tyrosine kinase family, predominantly expressed in neuronal tissue [1]. Due to intra- and inter-chromosomal translocations, NTRK can undergo chromosomal rearrangements resulting in gene fusions. This leads to ligand independent constitutive activation of the TRK pathway which can potentially be oncogenic [2]. Though, NTRK fusions remain rare genetic events found in tumors. These gene fusions can represent targetable alterations. The Food and Drug Administration (FDA) approved the first-generation TRK-inhibitors, such as LOXO-101 (larotrectinib) [9] and entrectinib [10], for the treatment of tumors that harbor NTRK fusions. This paper gives an overview of the diagnostic challenges and the clinical importance of NTRK fusions in tumors, with special emphasis on sarcomas
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