ssmuБюллетень сибирской медициныBulletin of Siberian Medicine1682-03631819-3684Siberian State Medical University, the Ministry of Healthcare of the Russian Federation10.20538/1682-0363-2026-3-111-123ssmu-6610Research ArticleОБЗОРЫ И ЛЕКЦИИREVIEW AND LECTURESСовременные представления о молекулярных механизмах резистентности к таргетной aHTu-HER2 терапии рака молочной железыCurrent Understanding of the Molecular Mechanisms of Resistance to Targeted Anti-HER2 Breast Cancer Therapyhttps://orcid.org/0000-0001-5281-7758БрагинаО. Д.BraginaO. D.

Брагина Ольга Дмитриевна д-р мед. наук, врач-онколог, вед. науч. сотрудник, отделение радионуклидной терапии и диагностики, НИИ онкологии, Томский НИМЦ; ст. науч. сотрудник, Научно-исследовательский центр «Онкотераностика», НИ ТПУ

634009, Томск, пер. Кооперативный, 5,

634050, Томск, пр. Ленина, 30

5 Kooperativny St., 634009 Tomsk,

30 Lenin Ave., 634050 Tomsk

bragina_od@mail.ruhttps://orcid.org/0009-0003-8559-6375СитниковаЕ. Ю.SitnikovaE. Yu.

Ситникова Екатерина Юрьевна врач-ординатор по специальности «Онкология», НИИ онкологии, Томский НИМЦ; асси­стент, кафедра онкологии, СибГМУ

634009, Томск, пер. Кооперативный, 5,

634050, Томск, Московский тракт, 2

5 Kooperativny St., 634009 Tomsk,

2 Moskovsky trakt, 634050 Tomsk

sitnikova_katerina00@mail.ruhttps://orcid.org/0009-0000-1661-7396НесыновА. А.NesynovA. A.

Несынов Александр Александрович врач-онколог, мл. науч. сотрудник, отделение системной и персонализированной терапии опухолей

634009, Томск, пер. Кооперативный, 5

5 Kooperativny St., 634009 Tomsk

nesynov.alex@mail.ruhttps://orcid.org/0000-0002-9468-1980ПаталякС. В.PatalyakS. V.

Паталяк Станислав Викторович канд. мед. наук, врач-онколог, зав. отделением системной и персонализированной те­рапии опухолей, НИИ онкологии, Томский НИМЦ; доцент кафедры онкологии, СибГМУ

634009, Томск, пер. Кооперативный, 5,

634050, Томск, Московский тракт, 2

5 Kooperativny St., 634009 Tomsk,

2 Moskovsky trakt, 634050 Tomsk

patalyak@gmail.comhttps://orcid.org/0000-0003-2061-8417ТаширеваЛ. А.TashirevaL. A.

Таширева Любовь Александровна д-р мед. наук, зав. лабораторией молекулярной терапии рака

634009, Томск, пер. Кооперативный, 5

5 Kooperativny St., 634009 Tomsk

 

tashireva@oncology.tomsk.ruНаучно-исследовательский институт (НИИ) онкологии Томского национального исследовательского медицинского центра (НИМЦ) Российской академии наук; Национальный исследовательский Томский политехнический университет (НИ ТПУ)РоссияCancer Research Institute, Tomsk National Research Medical Center (NRMC), Russian Academy of Sciences; National Research Tomsk Polytechnic University (NR TPU)Russian FederationНаучно-исследовательский институт (НИИ) онкологии Томского национального исследовательского медицинского центра (НИМЦ) Российской академии наук; Сибирский государственный медицинский университет (СибГМУ)РоссияCancer Research Institute, Tomsk National Research Medical Center (NRMC), Russian Academy of Sciences; Siberian State Medical UniversityRussian FederationНаучно-исследовательский институт (НИИ) онкологии Томского национального исследовательского медицинского центра (НИМЦ) Российской академии наукРоссияCancer Research Institute, Tomsk National Research Medical Center (NRMC), Russian Academy of SciencesRussian Federation202601102026253111123Copyright © Брагина О.Д., Ситникова Е.Ю., Несынов А.А., Паталяк С.В., Таширева Л.А., 20262026Брагина О.Д., Ситникова Е.Ю., Несынов А.А., Паталяк С.В., Таширева Л.А.Bragina O.D., Sitnikova E.Y., Nesynov A.A., Patalyak S.V., Tashireva L.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://bulletin.ssmu.ru/jour/article/view/6610

В лекции обобщены современные данные о молекулярных и генетических механизмах резистентности к таргетной анти-НЕКЗ терапии рака молочной железы (РМЖ), которая, несмотря на объективные успехи, остается неоптимальной. Так, в течение первых двух лет после завершения комбинированного лечения у 10-15% больных развиваются локорегиональные рецидивы, а у 15-25% пациентов в течение первых 5 лет динамического наблюдения отмечается отдаленное метастазирование, что обусловлено лекарствен­ной устойчивостью.

В качестве основных механизмов резистентности рассмотрены нарушение связывания таргетных препа­ратов с НЕК2-рецептором, активирующие мутации в гене HER2, внутриопухолевая гетерогенность HER2, перекрестное взаимодействие между HER2 и рецепторами эстрогена, нарушение внутриклеточной переда­чи сигналов, а также роли гетеродимера HER2-HER3 и опухолевого микроокружения. Отдельное внимание уделено факторам, ограничивающим эффективность конъюгатов моноклональных антител с цитостатика­ми, которые на сегодняшний день являются предметом активного изучения.

Понимание механизмов резистентности к анти-HER2 терапии имеет ключевое значение для оптимизации стратегий лечения больных HER2-положительным РМЖ, включая разработку новых препаратов, предот­вращение резистентности на начальных этапах, а также персонализацию терапии для улучшения прогноза данной категории пациентов.

This lecture summarizes current evidence on the molecular and genetic mechanisms of resistance to HER2targeted breast cancer (BC) therapies. Despite marked improvements in HER2-positive BC treatment, the efficacy of targeted therapy remains suboptimal. Within the first two years after completing combined therapy, 10-15% of patients develop locoregional recurrences, and 15-25% of patients develop distant metastases within the first five years of follow-up, which is attributed to drug resistance.

The primary mechanisms of resistance are discussed, including impaired binding of targeted drugs to HER2, activating HER2 mutations, HER2 intratumoral heterogeneity, cross-talk between HER2 and estrogen receptors, alterations in intracellular signaling pathways, the role of HER2-HER3 heterodimer, and the tumor microenvironment. Particular emphasis is placed on factors limiting the efficacy of antibody drug conjugates, which are currently a subject of active investigation. Understanding the mechanisms of resistance to HER2-targeted therapies is crucial for optimizing treatment strategies for HER2-positive BC patients. This includes novel drug development, early resistance prevention, and personalized therapy to improve patient outcomes.

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