oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2021-20-6-120-133oncotomsk-1995Research ArticleОБЗОРЫREVIEWSCтруктурные перестройки генов NTRK: характеристика, методы детекции и таргетная терапия онкологических заболеванийSructural rearrangements of NTRK genes: characteristics, methods of detection and targeted therapy for cancerhttps://orcid.org/0000-0002-4822-0251КечинА. А.KechinA. A.

 кандидат биологических наук, младший научный сотрудник лаборатории фармакогеномики

SPIN-код: 9252-8834. Researcher ID: K-2411-2017. Author ID (Scopus): 55377180600

 Россия, 630090, г. Новосибирск, пр. ак. Лаврентьева, 8 

 Россия, 630090, г. Новосибирск, ул. Пирогова, 2 

 PhD, Researcher

SPIN-код: 9252-8834. Researcher ID: K-2411-2017. Author ID (Scopus): 55377180600 

8, Lavrentiev Av., Novosibirsk, 630090, Russia

2, Pirogova St., Novosibirsk, 630090, Russia

aa_kechin@niboch.nsc.ruАндрияноваА. И.AndriyanovaA. I.

 бакалавр 

 Россия, 630090, г. Новосибирск, ул. Пирогова, 2 

 Bachelor 

2, Pirogova St., Novosibirsk, 630090, Russia

https://orcid.org/0000-0002-8950-5368ФилипенкоМ. Л.FilipenkoM. L.

 заведующий лабораторией фармакогеномики

SPIN-код: 4025-0533. Researcher ID: AAU-9552-2020. Author ID (Scopus): 8714462300

 Россия, 630090, г. Новосибирск, пр. ак. Лаврентьева, 8 

 Россия, 630090, г. Новосибирск, ул. Пирогова, 2 

 PhD, Head of Laboratory

SPIN-код: 4025-0533. Researcher ID: AAU-9552-2020. Author ID (Scopus): 8714462300 

8, Lavrentiev Av., Novosibirsk, 630090, Russia

2, Pirogova St., Novosibirsk, 630090, Russia

Институт химической биологии и фундаментальной медицины Сибирского отделения Российской академии наук; Новосибирский государственный университетРоссияInstitute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences; Novosibirsk State UniversityRussian FederationНовосибирский государственный университетРоссияNovosibirsk State UniversityRussian Federation202113012022206120133Copyright © Кечин А.А., Андриянова А.И., Филипенко М.Л., 20222022Кечин А.А., Андриянова А.И., Филипенко М.Л.Kechin A.A., Andriyanova A.I., Filipenko M.L.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/1995

Введение. В ноябре 2018 г. Fdaодобрило применение ларотректениба для лечения распространенных солидных опухолей, содержащих слияния с генами NTRK других генов, в августе 2019 г. – энтректиниб. Цель исследования – представить современные данные о структуре и функциях генов NTRK, частоте встречаемости перестроек с их участием, последствиях от их возникновения на клеточном уровне, методах детекции таких перестроек, а также о таргетных препаратах, применяемых при наличии химерных генов NTRK. Материал и методы. Поиск статей осуществлялся в базах данных pubmed NcBi, Web of science, scopus. Результаты. Продукты генов NTRK являются рецепторами к нейротрофинам, и их высокая экспрессия в норме наблюдается только в узком диапазоне типов тканей. Внутрихромосомные или межхромосомные перестройки приводят к значительному повышению уровня экспрессии химерного гена благодаря попаданию под сильный промотор гена-партнера. Высокая транскрипционная активность такого гена наряду с постоянным включением киназной активности белкового продукта приводят к включению метаболических путей, отвечающих за уход клетки от апоптоза и нарушение регуляции клеточного цикла. Встречаемость химерных генов NTRK варьирует между различными типами опухолей, с наиболее высокой (до 90 %) – при редко встречающихся онкологических заболеваниях (секреторная карцинома молочной железы, секреторная карцинома слюнных желез, врождённая мезобластическая нефрома, детская фибросаркома). Новые таргетные препараты (ларотректениб и энтректиниб) имеют высокую эффективность подавления роста опухоли, несущей перестройки NTRK, вне зависимости от типа опухоли. В связи с этим актуальными представляются внедрение новых высокоточных методов детекции химерных генов NTRK, а также исследование механизмов развития резистентности с предположением способов ее преодоления. Заключение. Перестройки генов NTRK встречаются достаточно часто при различных видах онкологии и являются эффективной мишенью для современных таргетных препаратов.

Background. The first-generation trk inhibitors, larotrectinib and entrectinib, were approved by the u.s. Food and drug administration (Fda) for the treatment of advanced solid tumors harboring NTRK gene fusions in November 2018 and in august 2019, respectively. The purpose of the study was to present upto-date data on the structure and functions of ntrk genes, the frequency of occurrence of rearrangements with their participation, the consequences of their occurrence at the cellular level, methods of detecting such rearrangements, as well as targeted drugs used in the presence of chimeric NTRK genes. Material and methods. A systemic literature search was conducted in pubmed ncbi, Web of science, scopus databases. Results. The products of NTRK genes are receptors for neurotrophins, and their high expression is normally observed only in a narrow range of tissue types. Intrachromosomal or interchromosomal rearrangements lead to a significant increase in the level of expression of the chimeric gene regulated by the strong promoter of the partner gene. The high transcriptional activity of such a gene, along with the constant activation of the kinase activity of the protein product, leads to the activation of metabolic pathways responsible for cell escape from apoptosis and disruption of the regulation of the cell cycle. The occurrence of chimeric NTRK genes varies between different types of tumors, with the highest (up to 90 %) in rare cancers (secretory carcinoma of the breast, secretory carcinoma of the salivary glands, congenital mesoblastic nephroma, children’s fibrosarcoma). Larotrectinib and entrectinib are highly effective targeted drugs in suppressing the growth of a tumor carrying NTRK rearrangements, regardless of the type of tumor. In this regard, the introduction of new high-precision methods for the detection of chimeric NTRK genes, as well as the study of the mechanisms of the development of resistance with the assumption of ways to overcome it, seems relevant. Conclusion. Rearrangements of NTRK genes are quite common in various types of oncology and are an effective target for modern targeted drugs.

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The authors declare that there are no conflicts of interest present.