Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K.
Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K.
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DOI：
10.1016/j.ccr.2010.11.023
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发表时间：
2010-12-14
期刊：
影响因子：
50.3
通讯作者：
Herlyn M
中科院分区：
文献类型：
--
作者：
Villanueva J;Vultur A;Lee JT;Somasundaram R;Fukunaga-Kalabis M;Cipolla AK;Wubbenhorst B;Xu X;Gimotty PA;Kee D;Santiago-Walker AE;Letrero R;D'Andrea K;Pushparajan A;Hayden JE;Brown KD;Laquerre S;McArthur GA;Sosman JA;Nathanson KL;Herlyn M
BRAF是黑色素瘤药物开发的一个有吸引力的靶点。然而，对BRAF抑制剂的耐药性是一个重大的临床挑战。我们描述了一种对BRAF抑制剂耐药的模型，该模型是通过用BRAF抑制剂SB-590885长期治疗BRAFV 600 E黑色素瘤细胞开发的;这些细胞对其他BRAF选择性抑制剂具有交叉耐药。抗性涉及三种RAF亚型之间的灵活转换，强调了黑色素瘤细胞适应药理学挑战的能力。IGF-1 R/PI 3 K信号在耐药黑色素瘤中增强，IGF-1 R/PI 3 K和MEK抑制剂的联合治疗诱导BRAF耐药细胞死亡。复发后人类肿瘤样本中IGFR-1 R和pAKT水平的增加与IGF-1 R/PI 3 K依赖性生存在BRAF抑制剂耐药性发展中的作用一致。
BRAF is an attractive target for melanoma drug development. However, resistance to BRAF inhibitors is a significant clinical challenge. We describe a model of resistance to BRAF inhibitors developed by chronic treatment of BRAFV600E melanoma cells with the BRAF inhibitor SB-590885; these cells are cross resistant to other BRAF-selective inhibitors. Resistance involves flexible switching among the three RAF isoforms, underscoring the ability of melanoma cells to adapt to pharmacological challenges. IGF-1R/PI3K signaling was enhanced in resistant melanomas, and combined treatment with IGF-1R/PI3K and MEK inhibitors induced death of BRAF inhibitor-resistant cells. Increased IGFR-1R and pAKT levels in a post-relapse human tumor sample are consistent with a role for IGF-1R/PI3K-dependent survival in the development of resistance to BRAF inhibitors.
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影响因子：
64.5
作者：
Heidorn SJ;Milagre C;Whittaker S;Nourry A;Niculescu-Duvas I;Dhomen N;Hussain J;Reis-Filho JS;Springer CJ;Pritchard C;Marais R
通讯作者：
Marais R
影响因子：
158.5
作者：
Kobayashi, S;Boggon, TJ;Halmos, B
通讯作者：
Halmos, B
影响因子：
64.8
作者：
通讯作者：
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影响因子：
6.5
作者：
Hilmi, Caroline;Larribere, Lionel;Bertolotto, Corine
通讯作者：
Bertolotto, Corine
影响因子：
4.2
作者：
Knight, Steven D.;Adams, Nicholas D.;Dhanak, Dashyant
通讯作者：
Dhanak, Dashyant