美国加州大学圣地亚哥分校的科学家鉴定了一种药物研发方法，该方法使快速增长的癌细胞得以消灭，而不会造成当前癌症疗法所产生的某些副作用。相关研究论文发表在11月13日《自然—医学》杂志上。
当前癌症药物结合目标酶RAF（该酶对细胞繁殖和肿瘤生长至关重要）时，会锚定多个位点，从而导致不可意料的副作用。该研究领导者David A. Cheresh与其同事设计了一种新的RAF 抑制因子，不结合RAF活性位点而是改变其结构，从而使其失活。
Cheresh表示：“该发现非比寻常，真正挑战了当前的教条。”研究者们希望该方法尽快尽快在临床应用。(生物谷 Bioon.com)
doi:10.1038/nm.2464
PMC:
PMID:
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.
