Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
Cancer Cell. 2011 Dec 13;20(6):715-27. doi: 10.1016/j.ccr.2011.11.004.
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.
我们表明伊马替尼、尼罗替尼和达沙替尼对 RAF 具有较弱的非靶点活性，因此以 RAS 依赖性的方式驱动 BRAF 和 CRAF 的反常激活。关键的是，由于 RAS 被 BCR-ABL 激活，在这些药物存在的情况下，耐药性慢性髓性白血病 (CML) 细胞中的 RAS 活性持续存在，驱动 BRAF、 CRAF、MEK 和 ERK 的反常激活，并导致对该途径的意外依赖性。因此，尼罗替尼与 MEK 抑制剂协同作用，可杀死耐药性 CML 细胞并阻止小鼠肿瘤生长。因此，我们表明伊马替尼、尼罗替尼和达沙替尼驱动反常 RAF/MEK/ERK 通路激活，并揭示了一种合成致死相互作用，可用于体外和体内杀死耐药性 CML 细胞。
