Erratum: Author correction to "Development of small-molecule tropomyosin receptor kinase (TRK) inhibitors for NTRK fusion cancers" [Acta Pharmaceutica Sinica B 11 (2021) 355-372].
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SUBMITTER: Jiang T
PROVIDER: S-EPMC9214051 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
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Erratum: Author correction to "Development of small-molecule tropomyosin receptor kinase (TRK) inhibitors for NTRK fusion cancers" [Acta Pharmaceutica Sinica B 11 (2021) 355-372].
Jiang Tingting T Wang Guan G Liu Yao Y Feng Lu L Wang Meng M Liu Jie J Chen Yi Y Ouyang Liang L
Acta pharmaceutica Sinica. B 20220302 6
[This corrects the article DOI: 10.1016/j.apsb.2020.05.004.]. ...[more]
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Project description:Tropomyosin receptor kinase A, B and C (TRKA, TRKB and TRKC), which are well-known members of the cell surface receptor tyrosine kinase (RTK) family, are encoded by the neurotrophic receptor tyrosine kinase 1, 2 and 3 (NTRK1, NTRK2 and NTRK3) genes, respectively. TRKs can regulate cell proliferation, differentiation and even apoptosis through the RAS/MAPKs, PI3K/AKT and PLCγ pathways. Gene fusions involving NTRK act as oncogenic drivers of a broad diversity of adult and pediatric tumors, and TRKs have become promising antitumor targets. Therefore, achieving a comprehensive understanding of TRKs and relevant TRK inhibitors should be urgently pursued for the further development of novel TRK inhibitors for potential clinical applications. This review focuses on summarizing the biological functions of TRKs and NTRK fusion proteins, the development of small-molecule TRK inhibitors with different chemotypes and their activity and selectivity, and the potential therapeutic applications of these inhibitors for future cancer drug discovery efforts.
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Project description:The neurotrophic tyrosine kinase receptor (NTRK) gene family is of rising importance as their fusions are oncogenic, and specific target drugs are available to inhibit the chimera proteins. Pan-TRK antibody, which shows the overexpression of the NTRK1-2-3 genes, is a useful tool to detect tumors with or without NTRK gene alterations, due to high negative predictive value. Though it is well known that pan-TRK immunopositivity is usually not connected to NTRK fusion, the role of other possible genetic alterations is under-researched. In our previous work, we found 3 NTRK1 amplified cases out of 6 cases with recurrent NTRK1 tyrosine kinase domain mutation pair, so we extended our investigation to a larger series to estimate amplification frequency. Pan-TRK immunopositivity was seen in 76 of the 132 dedifferentiated liposarcomas cases, followed by NTRK1-2-3 break-apart FISH tests in 76 pan-TRK positive cases to detect oncogenic fusions or other copy number alterations of these genes. None of the pan-TRK immunopositive dedifferentiated liposarcomas showed absolutely certain sign of fusion, however, 18 (28%) cases showed amplification of one of the genes, 13 had polysomy, 34 were normal, 11 were not evaluable. The extent of pan-TRK immunoreaction showed a positive correlation (p = 0.002) with the NTRK status found by FISH. Analyzing publicly available data from large series of 265 liposarcoma samples consisting of both well-differentiated and dedifferentiated liposarcoma case, 23 (8.6%) cases showed a mutual exclusive amplification of the NTRK genomic loci in a non-preselected, independent patient population indicating that our findings are presented in other cohorts. Our results underline the so far not revealed frequent occurrence of NTRK amplifications which might be important in the TRK inhibition therapy.
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Project description:NTRK fusions are rare oncogenic drivers that occur across a range of pediatric cancers. These include infantile fibrosarcoma and secretory breast cancer in which such fusions are nearly pathognomonic, and a spectrum of more common pediatric cancers in which NTRK fusions occur at a lower frequency. Within the last 5 years, two TRK inhibitors, larotrectinib and entrectinib, have demonstrated histology-agnostic activity against NTRK fusion driven cancers and achieved FDA approval. Here the data supporting the use of these TRK inhibitors for the treatment of cancers harboring NTRK fusions is reviewed, with a particular focus on the pediatric experience. Mechanisms of acquired resistance to these first generation TRK inhibitors are discussed and investigational second generation TRK inhibitors that may overcome some of these mechanisms of resistance are highlighted.
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