ETV6-NTRK3 gene fusion

ETV6-NTRK3 gene fusion is the translocation of genetic material between the ETV6 gene located on the short arm (designated p) of chromosome 12 at position p13.2 (i.e. 12p13.2) and the NTRK3 gene located on the long arm (designated q) of chromosome 15 at position q25.3 (i.e. 15q25.3) to create the (12;15)(p13;q25) fusion gene, ETV6-NTRK3. This new gene consists of the 5' end of ETV6 fused to the 3' end of NTRK3.[1] ETV6-NTRK3 therefore codes for a chimeric oncoprotein consisting of the helix-loop-helix (HLH) protein dimerization domain of the ETV6 protein fused to the tyrosine kinase (i.e. PTK) domain of the NTRK3 protein.[2] The ETV6 gene codes for the transcription factor protein, ETV6, which suppresses the expression of, and thereby regulates, various genes that in mice are required for normal hematopoiesis as well as the development and maintenance of the vascular network.[3] NTRK3 codes for Tropomyosin receptor kinase C a NT-3 growth factor receptor cell surface protein that when bound to its growth factor ligand, neurotrophin-3, becomes an active tyrosine kinase that phosphorylates tyrosine residues on, and thereby stimulates, signaling proteins that promote the growth, survival, and proliferation of their parent cells. The tyrosine kinase of the ETV6-NTRK3 fusion protein is dysfunctional in that it is continuously active in phosphorylating tyrosine residues on, and thereby continuously stimulating, proteins that promote the growth, survival, and proliferation of their parent cells. In consequence, these cells take on malignant characteristics and are on the pathway of becoming cancerous.[4][5] Indeed, the ETV6-NTRK3 fusion gene appears to be a critical driver of several types of cancers. It was originally identified in congenital fibrosarcoma[1] and subsequently found in mammary secretory carcinoma (also termed juvenile breast cancer), mammary analogue secretory carcinoma of salivary glands (also termed MASC or MASCSG), salivary gland–type carcinoma of the thyroid, secretory carcinoma of the skin, congenital fibrosarcoma, congenital mesoblastic nephroma, rare cases of acute myelogenous leukemia, ALK-negative Inflammatory myofibroblastic tumour, cholangiocarcinoma,[6] and radiation-induced papillary thyroid carcinoma.[7][8][9][10][11][12][13]

NTRK3 inhibitors in clinical development

Because cancers associated with the expression of the ETV6-NTRK3 fusion protein are known or suspected of being a direct consequence of overly active ETV6-NTRK3's tyrosine kinase, it has been proposed that tyrosine kinase inhibitors with specificity for NTRK3 may be of therapeutic usefulness in these cancers. Entrectinib is a pan-NTRK as well as an ALK and ROS1 tyrosine kinase inhibitor has been found useful in treating a single patient with ETV6-NRTK3 fusion gene-associated mammary analogue secretory carcinoma and has lend support to the clinical development of NTRK3-directed tyrosine kinase inhibitors to treat ETV6-NTRK3 fusion protein associated malignancies.[10] Three clinical trials are in the recruitment phase for determining the efficacy of treating a wide range of solid tumors associated with mutated overactive tyrosine kinase proteins, including the ETV6-TRK3 protein, with larotrectinib, a non-selective inhibitor of NTRK1, NTRK2, and NTRK3 tyrosine kinases.[14] Larotrectinib was approved by the FDA on November 26, 2018.

References
  1. Knezevich SR, McFadden DE, Tao W, Lim JF, Sorensen PH (February 1998). "A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma". Nature Genetics. 18 (2): 184–7. doi:10.1038/ng0298-184. PMID 9462753. S2CID 7390311.
  2. Wai DH, Knezevich SR, Lucas T, Jansen B, Kay RJ, Sorensen PH (February 2000). "The ETV6-NTRK3 gene fusion encodes a chimeric protein tyrosine kinase that transforms NIH3T3 cells". Oncogene. 19 (7): 906–15. doi:10.1038/sj.onc.1203396. PMID 10702799.
  3. De Braekeleer E, Douet-Guilbert N, Morel F, Le Bris MJ, Basinko A, De Braekeleer M (August 2012). "ETV6 fusion genes in hematological malignancies: a review". Leukemia Research. 36 (8): 945–61. doi:10.1016/j.leukres.2012.04.010. PMID 22578774.
  4. Stenman G (July 2013). "Fusion oncogenes in salivary gland tumors: molecular and clinical consequences". Head and Neck Pathology. 7 Suppl 1: S12–9. doi:10.1007/s12105-013-0462-z. PMC 3712096. PMID 23821214.
  5. Lu H, Villafane N, Dogruluk T, Grzeskowiak CL, Kong K, Tsang YH, Zagorodna O, Pantazi A, Yang L, Neill NJ, Kim YW, Creighton CJ, Verhaak RG, Mills GB, Park PJ, Kucherlapati R, Scott KL (July 2017). "Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer". Cancer Research. 77 (13): 3502–3512. doi:10.1158/0008-5472.CAN-16-2745. PMC 5568774. PMID 28512244.
  6. Demols, Anne; Rocq, Laureen; Charry, Manon; De Nève, Nancy; Verrellen, Audrey; Ramadhan, Ali; Van Campenhout, Claude; De Clercq, Sarah; Salmon, Isabelle; D'Haene, Nicky (2020-02-01). "NTRK gene fusions in biliary tract cancers". Journal of Clinical Oncology. 38 (4_suppl): 574. doi:10.1200/JCO.2020.38.4_suppl.574. ISSN 0732-183X. S2CID 213009984.
  7. Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, Mathers JA, Becker L, Carneiro F, MacPherson N, Horsman D, Poremba C, Sorensen PH (November 2002). "Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma". Cancer Cell. 2 (5): 367–76. doi:10.1016/S1535-6108(02)00180-0. PMID 12450792.
  8. Majewska H, Skálová A, Stodulski D, Klimková A, Steiner P, Stankiewicz C, Biernat W. "Mammary analogue secretory carcinoma of salivary glands: a new entity associated with ETV6 gene rearrangement." Virchows Arch. 2015 Mar;466(3):245-54. doi: 10.1007/s00428-014-1701-8. Epub 2014 Dec 12.
  9. Argani P, Fritsch M, Kadkol SS, Schuster A, Beckwith JB, Perlman EJ (January 2000). "Detection of the ETV6-NTRK3 chimeric RNA of infantile fibrosarcoma/cellular congenital mesoblastic nephroma in paraffin-embedded tissue: application to challenging pediatric renal stromal tumors". Modern Pathology. 13 (1): 29–36. doi:10.1038/modpathol.3880006. PMID 10658907.
  10. Khotskaya YB, Holla VR, Farago AF, Mills Shaw KR, Meric-Bernstam F, Hong DS (May 2017). "Targeting TRK family proteins in cancer". Pharmacology & Therapeutics. 173: 58–66. doi:10.1016/j.pharmthera.2017.02.006. PMID 28174090. S2CID 4243668.
  11. Skalova A, Michal M, Simpson RH (January 2017). "Newly described salivary gland tumors". Modern Pathology. 30 (s1): S27–S43. doi:10.1038/modpathol.2016.167. PMID 28060365.
  12. Baloch ZW, Asa SL, Barletta JA, Ghossein RA, Juhlin CC, Jung CK, LiVolsi VA, Papotti MG, Sobrinho-Simões M, Tallini G, Mete O (March 2022). "Overview of the 2022 WHO Classification of Thyroid Neoplasms". Endocrine Pathology. 33 (1): 27–63. doi:10.1007/s12022-022-09707-3. PMID 35288841. S2CID 247440666.
  13. Bishop JA, Taube JM, Su A, Binder SW, Kazakov DV, Michal M, Westra WH (January 2017). "Secretory Carcinoma of the Skin Harboring ETV6 Gene Fusions: A Cutaneous Analogue to Secretory Carcinomas of the Breast and Salivary Glands". The American Journal of Surgical Pathology. 41 (1): 62–66. doi:10.1097/PAS.0000000000000734. PMID 27631515. S2CID 23882212.
  14. "Search for ETV6-NTRK3". ClinicalTrials.gov.
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