11月14日,，據(jù)美國媒體報(bào)道，美國科學(xué)家研制出一種名為KG5的新藥,，能通過依附于酶RAF之上并改變其結(jié)構(gòu)來抑制幾乎所有腫瘤細(xì)胞的分裂,，從而破壞增生能力最強(qiáng)的腫瘤?？茖W(xué)家們表示：“這個(gè)非同尋常的新成果能真正挑戰(zhàn)現(xiàn)有的醫(yī)學(xué)教條,。”相關(guān)研究發(fā)表在11月13日出版的《自然·醫(yī)學(xué)》網(wǎng)絡(luò)版上。
目前攻擊RAF等酶的抗癌藥物一般都被設(shè)計(jì)成同酶的活性部位相互作用,，但這樣常常會(huì)使其缺乏針對性,。為避免現(xiàn)有藥物的限制，摩爾斯癌癥研究中心轉(zhuǎn)化醫(yī)學(xué)研究小組副主任,、病理學(xué)教授戴維·切瑞西領(lǐng)導(dǎo)的研究團(tuán)隊(duì)研制出新型RAF抑制劑KG5,。它可以改變酶的結(jié)構(gòu)讓酶失去活性。切瑞西表示：“盡管RAF已是科學(xué)家的‘老朋友’,，但它在對細(xì)胞增生和腫瘤生長非常關(guān)鍵的細(xì)胞分裂中的作用仍不為人所知悉,。通過設(shè)計(jì)出一種能改變RAF形狀的新型藥物，我們能揭示RAF在很多腫瘤中未被發(fā)現(xiàn)的作用,。”
測試結(jié)果表明,，KG5能在不斷增生的細(xì)胞中挑選出RAF，但會(huì)忽視正常的或沉默的細(xì)胞,。而且在受到其影響的腫瘤細(xì)胞中,，RAF不能同細(xì)胞有絲分裂器相互聯(lián)系來引導(dǎo)細(xì)胞分裂，從而致使腫瘤細(xì)胞凋亡,。另外,，KG5也能采用同樣的方式有效地干預(yù)血管新生，從而干預(yù)腫瘤的生長以及腫瘤的轉(zhuǎn)移,。切瑞西指出：“這個(gè)非同尋常的發(fā)現(xiàn)能真正挑戰(zhàn)現(xiàn)有的教條,。通過設(shè)計(jì)出‘繞過’酶的活性部位的新藥，我們找到了破壞腫瘤生長的新方法。從本質(zhì)上而言,，我們正在采用一種全新的方式攻擊一種重要的酶,。”
科學(xué)家們對癌細(xì)胞系、動(dòng)物模型以及從癌癥病人身上提取出來的活組織進(jìn)行了測試,，KG5都產(chǎn)生了同樣的結(jié)果,。
無論是射線療法還是藥物療法，人們對付癌細(xì)胞這個(gè)失去生長控制的惡魔的辦法不外乎兩個(gè)字：對抗,。美國科學(xué)家的新發(fā)現(xiàn)卻反其道而行之,，將你死我活的對抗轉(zhuǎn)化為用“藥品炮彈”來同化目標(biāo)酶。前者看似直接,，實(shí)際上卻不僅面臨著打擊精準(zhǔn)度不夠的問題,，還可能因?yàn)殚L期用藥帶來的抗藥性而使打擊強(qiáng)度下降。相比之下,，通過改變目標(biāo)酶的結(jié)構(gòu),、將其“同化”為無用的物質(zhì)，其優(yōu)異之處不言自明,?？茖W(xué)家需要進(jìn)一步確認(rèn)的，也許只是“同化”之后的產(chǎn)物在人體內(nèi)堆積是否會(huì)產(chǎn)生副作用,。（生物谷 Bioon.com）
doi:10.1038/nm.2464
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A MEK-independent role for CRAF in mitosis and tumor progression
inhoa Mielgo, Laetitia Seguin, Miller Huang, Maria Fernanda Camargo, Sudarshan Anand, Aleksandra Franovic, Sara M Weis, Sunil J Advani, Eric A Murphy & David A Cheresh
RAF kinases regulate cell proliferation and survival and can be dysregulated in tumors1, 2. The role of RAF in cell proliferation has been linked to its ability to activate mitogen-activated protein kinase kinase 1 (MEK) and mitogen-activated protein kinase 1 (ERK). Here we identify a MEK-independent role for RAF in tumor growth. Specifically, in mitotic cells, CRAF becomes phosphorylated on Ser338 and localizes to the mitotic spindle of proliferating tumor cells in vitro as well as in murine tumor models and in biopsies from individuals with cancer. Treatment of tumors with allosteric inhibitors, but not ATP-competitive RAF inhibitors, prevents CRAF phosphorylation on Ser338 and localization to the mitotic spindle and causes cell-cycle arrest at prometaphase. Furthermore, we identify phospho-Ser338 CRAF as a potential biomarker for tumor progression and a surrogate marker for allosteric RAF blockade. Mechanistically, CRAF, but not BRAF, associates with Aurora kinase A (Aurora-A) and Polo-like kinase 1 (Plk1) at the centrosomes and spindle poles during G2/M. Indeed, allosteric or genetic inhibition of phospho-Ser338 CRAF impairs Plk1 activation and accumulation at the kinetochores, causing prometaphase arrest, whereas a phospho-mimetic Ser338D CRAF mutant potentiates Plk1 activation, mitosis and tumor progression in mice. These findings show a previously undefined role for RAF in tumor progression beyond the RAF-MEK-ERK paradigm, opening new avenues for targeting RAF in cancer.
