Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press32710.17650/2313-805X-2021-8-1-10-16REVIEW ARTICLESОБЗОРНЫЕ СТАТЬИЕstrogen receptor α (ESR1) and SRC family kinase (LYN) gene's mutations associated with ovarian cancer endocrine therapy resistanceМутации в генах эстрогенового рецептора α (ESR1) и киназы семейства SRC (LYN), ассоциированные с резистентностью к гормонотерапии рака яичниковhttps://orcid.org/0000-0002-0158-4605ShestakovaE. A.ШестаковаЕ. А.
Russian Federation

Elena Anatolevna Shestakova

Moscow 115478

Елена Анатольевна Шестакова

115478 Москва, Каширское шоссе, 24

elenaanshestakova@mail.ruN.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation,ФГБУ «Национальный медицинский исследовательский центр онкологии имени Н.Н. Блохина» Минздрава России150120218110160805202108052021Copyright ©; 2021, Shestakova E.A.Copyright ©; 2021, Шестакова Е.А.2021Shestakova E.A.Шестакова Е.А.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/327

Recently multiple data accumulated concerning mutations in the ESR1 gene coding estrogen receptor α (mutESR1) and in the LYN gene coding non receptor tyrosine kinase SRC family member (mutLYN) that are associated with endocrine therapy resistance and that could be considered as markers of endocrine therapy efficiency. In case of gynecologic cancers including ovarian cancer the most frequent mutESR1 are ESR1L536H/P/R/V , ESR1Y537S/N/C/H, ESR1D538G that emerge in the course of hormonotherapy especially using aromatase inhibitors. mutLYN including LYNE159K, LYND189Y, LYNK209N, LYNA370T, LYNG418R, LYNA503D are also identified. mutESR1 and mutLYN increase transcriptional activity of estrogen receptor α (ERα) coded with ESR1 gene and catalytic activity of LYN kinase inducing endocrine therapy resistance. Interdependence of ESR1 and LYN genes is revealed at the level of proteins that they code as the kinases of the SRC family including LYN activate ERα-dependent transcription due to the phosphorylation of ERα at Y537 amino-acid residue that is the most frequently mutated in tumors with endocrine therapy resistance.

 The aim of the review is revealing the clinical correlations of mutESR1 and mutLYN with the ovarian cancer endocrine therapy resistance that opens perspectives of mutESR1 and mutLYN use as new predictive markers of ovarian cancer and development of more efficient anti-tumor medicaments. In the review the information obtained from PubMed database for the last 20 years using the following key words: ESR1, LYN, mutation(s), estrogen receptor α (ERα), LYN kinase, SRC family kinases, ovarian cancer, gynecologic(al) cancer is discussed.

В последнее время появляются многочисленные данные о мутациях в гене ESR1 (mutESR1), кодирующем эстрогеновый рецептор α (ЭРα), и  гене, кодирующем белок из  семейства SRC нерецепторных тирозинкиназ, LYN (mutLYN), ассоциированных с резистентностью опухолей к эндокринной терапии. Такие мутации могут рассматриваться в  качестве маркеров эффективности эндокринной терапии. В  случае гинекологических злокачественных новообразований, включая рак яичников, наиболее часто наблюдаются mutESR1, а именно ESR1L536H/P/R/V , ESR1Y537S/N/C/H, ESR1D538G, возникающие при лечении пациенток с использованием гормонотерапии, в  особенности ингибиторов ароматазы. Идентифицированы также mutLYN: LYNE159K, LYND189Y, LYNK209N, LYNA370T , LYNG418R, LYNA503D. Мутации в генах ESR1 и LYN ассоциированы с резистентностью к эндокринной терапии рака яичников, так как увеличивают транскрипционную активность ЭРα и каталитическую активность киназы LYN соответственно. Кроме того, наблюдается взаимосвязь генов ESR1 и LYN на уровне кодируемых ими белков, так как киназы семейства SRC, к которым относится LYN, активируют транскрипцию генов-мишеней ЭРα, фосфорилируя рецептор по аминокислотному остатку Y537. При этом в опухолях с резистентностью к эндокринной терапии наиболее часто выявляются мутации ЭРα по аминокислоте Y537.

Задачей обзорной статьи был анализ клинических корреляций mutESR1 и mutLYN и резистентности рака яичников к  эндокринной терапии, раскрывающий перспективы использования mutESR1 и mutLYN в  качестве новых предиктивных маркеров и поиска более эффективных противоопухолевых средств. Обсуждены данные, представленные в поисковой системе PubMed за последние 20 лет, полученные с использованием следующих ключевых слов: ESR1, LYN, mutation(s), estrogen receptor α (ERα), kinase LYN, SRC family kinases, ovarian cancer, gynecologic(al) cancer.

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