Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma.
Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma.
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作者：
B-RAF是人类癌症中最常见的突变蛋白激酶。BRAF中的致癌突变在黑色素瘤中很常见，随后证明这些肿瘤依赖于RAF/MEK/ERK途径，这一发现为抑制B-RAF激酶活性可能使黑色素瘤患者受益提供了希望。在此，我们描述了PLX 4032（RG 7204），一种致癌B-RAF激酶活性的有效抑制剂的结构指导发现。临床前实验表明，PLX 4032选择性阻断BRAF突变细胞中的RAF/MEK/ERK通路，并导致BRAF突变异种移植物消退。毒理学研究证实了与高度选择性一致的宽安全范围，使得能够使用PLX 4032的结晶制剂进行I期临床试验。在黑色素瘤患者亚组中，在治疗开始前和治疗两周后收集的配对活检标本中监测通路抑制。该分析揭示了ERK磷酸化的实质性抑制，但临床评价并未显示肿瘤消退。在新的无定形药物制剂提供的更高药物暴露下，患者肿瘤中ERK磷酸化的抑制大于80%与临床反应相关。事实上，1期临床数据显示，在960 mg每日两次口服剂量治疗的转移性黑色素瘤患者中，有效率高达81%。这些数据表明BRAF突变型黑色素瘤高度依赖于B-RAF激酶活性。
B-RAF is the most frequently mutated protein kinase in human cancers. The finding that oncogenic mutations in BRAF are common in melanoma followed by the demonstration that these tumors are dependent on the RAF/MEK/ERK pathway offered hope that inhibition of B-RAF kinase activity could benefit melanoma patients. Herein, we describe the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic B-RAF kinase activity. Preclinical experiments demonstrated that PLX4032 selectively blocked the RAF/MEK/ERK pathway in BRAF mutant cells and caused regression of BRAF mutant xenografts. Toxicology studies confirmed a wide safety margin consistent with the high degree of selectivity, enabling Phase 1 clinical trials using a crystalline formulation of PLX4032. In a subset of melanoma patients, pathway inhibition was monitored in paired biopsy specimens collected before treatment initiation and following two weeks of treatment. This analysis revealed substantial inhibition of ERK phosphorylation, yet clinical evaluation did not show tumor regressions. At higher drug exposures afforded by a new amorphous drug formulation, greater than 80% inhibition of ERK phosphorylation in the tumors of patients correlated with clinical response. Indeed, the Phase 1 clinical data revealed a remarkably high 81% response rate in metastatic melanoma patients treated at an oral dose of 960 mg twice daily. These data demonstrate that BRAF-mutant melanomas are highly dependent on B-RAF kinase activity.
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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：
64.8
作者：
Solit, DB;Garraway, LA;Rosen, N
通讯作者：
Rosen, N
影响因子：
7.4
作者：
Søndergaard JN;Nazarian R;Wang Q;Guo D;Hsueh T;Mok S;Sazegar H;MacConaill LE;Barretina JG;Kehoe SM;Attar N;von Euw E;Zuckerman JE;Chmielowski B;Comin-Anduix B;Koya RC;Mischel PS;Lo RS;Ribas A
通讯作者：
Ribas A
影响因子：
120.1
作者：
Koch, WH
通讯作者：
Koch, WH
DOI：
10.1073/pnas.0711741105
发表时间：
2008-02-26
影响因子：
11.1
作者：
Tsai, James;Lee, John T.;Bollag, Gideon
通讯作者：
Bollag, Gideon