Холангиоканцерогенез и таргетная терапия холангиокарциномы

Холангиокарцинома включает высоко гетерогенную группу злокачественных опухолей билиарного тракта, развивающихся из эпителия внутри- и внепеченочных желчных протоков. Заболеваемость холангиокарциномой растет во всем мире, и в настоящее время на долю ее приходится около 15% всех первичных опухолевых заболеваний печени и до 3% злокачественных новообразований желудочно-кишечного тракта. Бессимптомное, но весьма агрессивное течение этих опухолей в сочетании с низкой чувствительностью к цитотоксической терапии способствует достаточно высокой смертности от этого заболевания, составляющей до 2% в структуре онкологической смертности в мире. Высокая гетерогенность холангиокарциномы на геномном, эпигенетическом и молекулярном уровнях значительно снижает эффективность доступных методов лечения. В последние десятилетия разрабатываются новые диагностические инструменты и методы лечения, призванные улучшить результаты лечения больных холангиокарциномой. Распространенность мутаций гена BRAF ассоциирована с возникновением различных опухолей, в том числе холангиокарциномы. В настоящее время зарегистрировано более 30 мутаций в гене BRAF, обладающих онкогенным потенциалом. В  основном затрагивается кодон V600, происходит аминокислотная замена, которая в  конечном итоге приводит к тому, что белок BRAF становится постоянно активным, даже в отсутствие факторов роста. Дабрафениб – ингибитор белка BRAF, который в мутировавших клетках находится в постоянной гиперактивной форме. Применение дабрафениба в качестве монотерапии приводит к развитию резистентности через 6-7 месяцев. Для предотвращения резистентности дабрафениб используется вместе с траметинибом, ингибитором MEK, который также блокирует путь киназы Ras-Raf-MEK-MAPK. 

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