許多浸潤性乳腺癌細胞表面有很多人類表皮生長因子受體2（HER2），這將導致癌細胞不受控制地生長擴散。有多種抗體如曲妥珠單抗和帕妥珠單抗可以識別HER2，這在乳腺癌治療中已經(jīng)使用多年。然而，有些情況下這些抗體不能殺死癌細胞。相反，癌細胞可以使自己處于休眠狀態(tài)，這樣癌細胞在任何時間里都可以自由生長復制。為什么有時抗體治療對乳腺癌細胞無效呢？
2016年6月3日，英國《自然·通訊》雜志在線發(fā)表瑞士蘇黎世大學的研究報告，發(fā)現(xiàn)了為什么這些抗體只是減緩腫瘤的生長，而不能殺死癌細胞。HER2同時使用數(shù)個信號通路傳遞給癌細胞進行生長和分裂，但到目前為止抗體只能阻止其中一個信號通路，而其他信號通路仍然可以繼續(xù)工作。最重要的開放通路會通過中央樞紐RAS蛋白質(zhì)重新激活HER2發(fā)出的生長信號，隨后抗體就失去效果，癌細胞繼續(xù)擴散。
該研究已經(jīng)發(fā)現(xiàn)有效解決方案，可關(guān)掉癌癥細胞HER2同一時間內(nèi)釋放的所有信號。該研究設(shè)計了一種蛋白質(zhì)化合物，以特定方式同時結(jié)合自身到兩個HER2之間并改變其空間結(jié)構(gòu)，這種受體彎曲阻止任何傳輸?shù)桨┘毎麅?nèi)部的生長信號，最后導致癌細胞死亡。另一個優(yōu)點是該蛋白質(zhì)選擇性作用于癌細胞，這可確保有效殺死癌細胞但健康細胞完好無損。例如，新型蛋白質(zhì)化合物會遏制小鼠腫瘤細胞生長但對小鼠健康無害。
這種非常有效的新型蛋白質(zhì)化合物活性成分由幾個重復蛋白質(zhì)組成，易于生產(chǎn)，生物化學實驗室正在開發(fā)和創(chuàng)造非常相似的新藥，并盡快通過臨床試驗在患者中測試這種新藥功能。因此，既然已經(jīng)確定了HER2相關(guān)癌細胞的致命點，那么未來治療浸潤性腫瘤類型的乳腺癌會更有希望。
Nat Commun. 2016 Jun 3;7:11672.
Intermolecular biparatopic trapping of ErbB2 prevents compensatory activation of PI3K/AKT via RAS-p110 crosstalk.
Tamaskovic R, Schwill M, Nagy-Davidescu G, Jost C, Schaefer DC, Verdurmen WP, Schaefer JV, Honegger A, Plückthun A.
University of Zurich, Winterthurerstr. 190, Zurich 8057, Switzerland.
Compensatory mechanisms, such as relief of AKT-ErbB3-negative feedback, are known to desensitize ErbB2-dependent tumours to targeted therapy. Here we describe an adaptation mechanism leading to reactivation of the PI3K/AKT pathway during trastuzumab treatment, which occurs independently of ErbB3 re-phosphorylation. This signalling bypass of phospho-ErbB3 operates in ErbB2-overexpressing cells via RAS-PI3K crosstalk and is attributable to active ErbB2 homodimers. As demonstrated by dual blockade of ErbB2/RAS and ErbB3 by means of pharmacological inhibition, RNA interference or by specific protein binders obstructing the RAS-p110α interaction, both routes must be blocked to prevent reactivation of the PI3K/AKT pathway. Applying these general principles, we developed biparatopic designed ankyrin repeat proteins (DARPins) trapping ErbB2 in a dimerization-incompetent state, which entail pan-ErbB inhibition and a permanent OFF state in the oncogenic signalling, thereby triggering extensive apoptosis in ErbB2-addicted tumours. Thus, these novel insights into mechanisms underlying network robustness provide a guide for overcoming adaptation response to ErbB2/ErbB3-targeted therapy.
PMID: 27255951
DOI: 10.1038/ncomms11672
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