BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation.
BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation.
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DOI：
10.1126/scisignal.2001148
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发表时间：
2010-11-23
影响因子：
7.3
通讯作者：
Engelman JA
中科院分区：
文献类型：
--
作者：
Corcoran RB;Dias-Santagata D;Bergethon K;Iafrate AJ;Settleman J;Engelman JA
致癌的BRAF突变在几种肿瘤类型中被发现，包括黑色素瘤和结直肠癌。具有BRAF突变的肿瘤具有更高的丝裂原激活蛋白激酶途径活性，并对BRAF和MEK(丝裂原激活或细胞外信号调节蛋白激酶)抑制剂的敏感性增加。为了确定获得性耐药的可能机制，我们从两个对MEK或BRAF抑制高度敏感的BRAF V600E突变结直肠癌细胞系中获得了对变构MEK抑制剂AZD6244具有抗性的克隆。这些对BRAF抑制剂表现出交叉抗性的AZD6244抗性(AR)克隆是通过扩增BRAF基因获得抗性的。一小部分未经处理的亲代细胞显示出预先存在的BRAF扩增。我们在BRAF突变的结直肠癌的细胞亚群中观察到类似的扩增。在细胞系中，BRAF扩增增加了磷酸化的MEK的丰度，并削弱了AZD6244抑制ERK(细胞外信号调节激酶)磷酸化的能力。AZD6244在AR细胞中抑制ERK磷酸化的能力可以通过低浓度的BRAF抑制剂处理来恢复，该抑制剂将磷酸化的MEK丰度减少到亲本细胞中观察到的量。联合抑制MEK和BRAF完全克服了单独使用MEK或BRAF抑制剂的耐药性，与单独使用任何一种抑制剂相比，在亲本细胞中也更有效。这些发现表明BRAF扩增是MEK和BRAF抑制剂耐药的一种机制，并建议联合抑制MEK和BRAF作为克服或可能阻止这种耐药机制的临床策略。
Oncogenic BRAF mutations are found in several tumor types, including melanomas and colorectal cancers. Tumors with BRAF mutations have increased mitogen-activated protein kinase pathway activity and heightened sensitivity to BRAF and MEK (mitogen-activated or extracellular signal–regulated protein kinase kinase) inhibitors. To identify potential mechanisms of acquired drug resistance, we generated clones resistant to the allosteric MEK inhibitor AZD6244 from two BRAF V600E mutant colorectal cancer cell lines that are highly sensitive to MEK or BRAF inhibition. These AZD6244-resistant (AR) clones, which exhibited cross-resistance to BRAF inhibitors, acquired resistance through amplification of the BRAF gene. A small percentage of treatment-naïve parental cells showed preexisting BRAF amplification. We observed similar amplification in a subset of cells in a BRAF-mutant colorectal cancer. In cell lines, BRAF amplification increased the abundance of phosphorylated MEK and impaired the ability of AZD6244 to inhibit ERK (extracellular signal–regulated kinase) phosphorylation. The ability of AZD6244 to inhibit ERK phosphorylation in AR cells was restored by treatment with a BRAF inhibitor at low concentrations that reduced the abundance of phosphorylated MEK to amounts observed in parental cells. Combined MEK and BRAF inhibition fully overcame resistance to MEK or BRAF inhibitors alone and was also more effective in parental cells compared to treatment with either inhibitor alone. These findings implicate BRAF amplification as a mechanism of resistance to both MEK and BRAF inhibitors and suggest combined MEK and BRAF inhibition as a clinical strategy to overcome, or possibly prevent, this mechanism of resistance.
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影响因子：
64.5
作者：
Azam, M;Latek, RR;Daley, GQ
通讯作者：
Daley, GQ
影响因子：
64.8
作者：
Solit, DB;Garraway, LA;Rosen, N
通讯作者：
Rosen, N
影响因子：
158.5
作者：
Kobayashi, S;Boggon, TJ;Halmos, B
通讯作者：
Halmos, B
影响因子：
64.5
作者：
Gupta PB;Onder TT;Jiang G;Tao K;Kuperwasser C;Weinberg RA;Lander ES
通讯作者：
Lander ES
影响因子：
5.7
作者：
Godin-Heymann, Nadia;LlIkus, Lindsey;Haber, Daniel A.
通讯作者：
Haber, Daniel A.