11月8日,，英國癌癥研究所宣布，根據(jù)他們發(fā)表在美國最新一期學(xué)術(shù)刊物Cancer Cell上的研究論文"Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukaemia"，對于慢性髓性白血病中有些癌細胞對常用治療藥物出現(xiàn)耐藥性的問題,，他們發(fā)現(xiàn)了可以通過添加另一種藥物來殺死這些癌細胞，從而保持治療的有效性。
據(jù)介紹,，慢性髓性白血病(chronic myeloid leukaemia, CML)是俗稱“血癌”的白血病中較常見的一種，現(xiàn)在常用的治療藥物是伊馬替尼和尼羅替尼,，但是有些癌細胞已對它們產(chǎn)生了耐藥性,，藥物不再能有效殺死這些癌細胞。
研究人員發(fā)現(xiàn),，一種名為MEK的蛋白質(zhì)在這些癌細胞的生存中發(fā)揮著重要作用,，使用能抑制這種蛋白質(zhì)功能的藥物有助于殺死癌細胞，如果聯(lián)合使用MEK抑制劑和尼羅替尼,，那些已產(chǎn)生耐藥性的慢性髓性白血病癌細胞也可以被殺死,。
參與研究的Richard Marais說，在慢性髓性白血病(chronic myeloid leukaemia, CML)的治療中耐藥性是個顯著問題,，本次研究為此找到了一種應(yīng)對方法,，接下來將通過人類臨床試驗測試這種方法的有效性。（生物谷Bioon.com）
doi:10.1016/j.ccr.2011.11.004
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Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukaemia
Leisl M. Packer, Sareena Rana, Robert Hayward, Thomas O'Hare, Christopher A. Eide, Ana Rebocho, Sonja Heidorn, Matthew S. Zabriskie, Ion Niculescu-Duvaz, Brian J. Druker, Caroline Springer, Richard Marais
We show that imatinib, nilotinib, and dasatinib possess weak off-target activity against RAF and, therefore, drive paradoxical activation of BRAF and CRAF in a RAS-dependent manner. Critically, because RAS is activated by BCR-ABL, in drug-resistant chronic myeloid leukemia (CML) cells, RAS activity persists in the presence of these drugs, driving paradoxical activation of BRAF, CRAF, MEK, and ERK, and leading to an unexpected dependency on the pathway. Consequently, nilotinib synergizes with MEK inhibitors to kill drug-resistant CML cells and block tumor growth in mice. Thus, we show that imatinib, nilotinib, and dasatinib drive paradoxical RAF/MEK/ERK pathway activation and have uncovered a synthetic lethal interaction that can be used to kill drug-resistant CML cells in vitro and in vivo.
