美國加州大學(xué)圣地亞哥分校的科學(xué)家鑒定了一種藥物研發(fā)方法,，該方法使快速增長的癌細胞得以消滅,，而不會造成當(dāng)前癌癥療法所產(chǎn)生的某些副作用。相關(guān)研究論文發(fā)表在11月13日《自然—醫(yī)學(xué)》雜志上,。
當(dāng)前癌癥藥物結(jié)合目標(biāo)酶RAF（該酶對細胞繁殖和腫瘤生長至關(guān)重要）時,，會錨定多個位點，從而導(dǎo)致不可意料的副作用,。該研究領(lǐng)導(dǎo)者David A. Cheresh與其同事設(shè)計了一種新的RAF 抑制因子,，不結(jié)合RAF活性位點而是改變其結(jié)構(gòu)，從而使其失活,。
Cheresh表示：“該發(fā)現(xiàn)非比尋常,，真正挑戰(zhàn)了當(dāng)前的教條,。”研究者們希望該方法盡快盡快在臨床應(yīng)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
Ainhoa Mielgo,1 Laetitia Seguin,1 Miller Huang,1 Maria Fernanda Camargo,1 Sudarshan Anand,1 Aleksandra Franovic,1 Sara M Weis,1 Sunil J Advani,2 Eric A Murphy1 & David A Cheresh1
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.
