Antitumor activity of the ERK inhibitor SCH772984 [corrected] against BRAF mutant, NRAS mutant and wild-type melanoma.
Antitumor activity of the ERK inhibitor SCH772984 [corrected] against BRAF mutant, NRAS mutant and wild-type melanoma.
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DOI：
10.1186/1476-4598-13-194
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发表时间：
2014-08-20
期刊：
影响因子：
37.3
通讯作者：
Ribas A
中科院分区：
文献类型：
--
作者：
Wong DJ;Robert L;Atefi MS;Lassen A;Avarappatt G;Cerniglia M;Avramis E;Tsoi J;Foulad D;Graeber TG;Comin-Anduix B;Samatar A;Lo RS;Ribas A
在黑色素瘤中，MAPK 通路的失调（通常通过 BRAFV600 或 NRASQ61 体细胞突变）导致组成型 ERK 信号传导。虽然 BRAF 抑制剂最初对 BRAF 突变型黑色素瘤有效，但目前尚无 FDA 批准的针对 BRAF 抑制剂耐药性 BRAFV600、NRAS 突变型或野生型黑色素瘤的靶向疗法。 SCH772984（一种新型 ERK1/2 抑制剂）的 50% 抑制浓度 (IC50) 在一组 50 个黑色素瘤细胞系中测定。通过蛋白质印迹法确定对 MAPK 和 AKT 信号传导的影响，并通过流式细胞术确定细胞周期。敏感性分为三组：敏感，50% 抑制浓度 (IC50) < 1 µM；中等敏感，IC50 1-2 μM；且耐药，>2 μM。 21 个 BRAF 突变体中有 15 个 (71%) 对 SCH772984 敏感，其中 4 个具有先天维莫非尼耐药性。所有三种 (100%) BRAF/NRAS 双突变体、14 个 NRAS 突变体中的 11 个 (78%) 和 7 个野生型黑色素瘤中的 5 个 (71%) 均敏感。在体外对维莫非尼产生耐药性的 BRAFV600 突变体中，以 MAPK 通路再激活为耐药机制的突变体对 SCH772984 敏感。 SCH772984 导致 G1 期停滞并诱导细胞凋亡。在 BRAF 突变黑色素瘤中联合使用 vemurafenib 和 SCH722984 在大多数细胞系中具有协同作用，并且在长期体外试验中显着延迟了获得性耐药的发生。因此，SCH772984在临床上可单独或与BRAF抑制剂联合用于治疗非BRAF突变型黑色素瘤或具有先天性或获得性耐药性的BRAF突变型黑色素瘤。本文的在线版本 (doi:10.1186/1476-4598-13-194) 包含补充材料，可供授权用户使用。
In melanoma, dysregulation of the MAPK pathway, usually via BRAFV600 or NRASQ61 somatic mutations, leads to constitutive ERK signaling. While BRAF inhibitors are initially effective for BRAF-mutant melanoma, no FDA-approved targeted therapies exist for BRAF-inhibitor-resistant BRAFV600, NRAS mutant, or wild-type melanoma. The 50% inhibitory concentration (IC50) of SCH772984, a novel inhibitor of ERK1/2, was determined in a panel of 50 melanoma cell lines. Effects on MAPK and AKT signaling by western blotting and cell cycle by flow cytometry were determined. Sensitivity fell into three groups: sensitive, 50% inhibitory concentration (IC50) < 1 μM; intermediately sensitive, IC50 1-2 μM; and resistant, >2 μM. Fifteen of 21 (71%) BRAF mutants, including 4 with innate vemurafenib resistance, were sensitive to SCH772984. All three (100%) BRAF/NRAS double mutants, 11 of 14 (78%) NRAS mutants and 5 of 7 (71%) wild-type melanomas were sensitive. Among BRAFV600 mutants with in vitro acquired resistance to vemurafenib, those with MAPK pathway reactivation as the mechanism of resistance were sensitive to SCH772984. SCH772984 caused G1 arrest and induced apoptosis. Combining vemurafenib and SCH722984 in BRAF mutant melanoma was synergistic in a majority of cell lines and significantly delayed the onset of acquired resistance in long term in vitro assays. Therefore, SCH772984 may be clinically applicable as a treatment for non-BRAF mutant melanoma or in BRAF-mutant melanoma with innate or acquired resistance, alone or in combination with BRAF inhibitors. The online version of this article (doi:10.1186/1476-4598-13-194) contains supplementary material, which is available to authorized users.
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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：
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8.8
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影响因子：
11.2
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Smalley, Keiran S. M.
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