EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib.
EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib.
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DOI：
10.1158/2159-8290.cd-11-0341
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发表时间：
2012-03
期刊：
影响因子：
28.2
通讯作者：
Engelman JA
中科院分区：
文献类型：
--
作者：
Corcoran RB;Ebi H;Turke AB;Coffee EM;Nishino M;Cogdill AP;Brown RD;Della Pelle P;Dias-Santagata D;Hung KE;Flaherty KT;Piris A;Wargo JA;Settleman J;Mino-Kenudson M;Engelman JA
BRAF突变发生在10-15%的结直肠癌（CRC）中，并带来不良后果。虽然RAF抑制剂如维罗非尼（PLX 4032）已被证明在BRAF突变型黑素瘤中有效，但它们在BRAF突变型CRC中令人惊讶地无效，并且这种差异的原因仍不清楚。与BRAF突变型黑色素瘤细胞相比，BRAF突变型CRC细胞对维罗非尼的敏感性较低，并且P-ERK抑制对治疗的响应不持续。尽管在CRC中观察到vemurafenib对磷酸化ERK的短暂抑制，但通过EGFR介导的RAS和CRAF激活发生了ERK快速再激活。BRAF突变型CRC表达的磷酸化EGFR水平高于BRAF突变型黑色素瘤，表明CRC特别适合EGFR介导的耐药。联合RAF和EGFR抑制阻断BRAF突变CRC细胞中MAPK信号转导的再激活，并显著提高体外和体内疗效。这些发现支持在BRAF突变型CRC患者中评价RAF和EGFR联合抑制。
BRAF mutations occur in 10–15% of colorectal cancers (CRCs) and confer adverse outcome. While RAF inhibitors such as vemurafenib (PLX4032) have proven effective in BRAF mutant melanoma, they are surprisingly ineffective in BRAF mutant CRCs, and the reason for this disparity remains unclear. Compared to BRAF mutant melanoma cells, BRAF mutant CRC cells were less sensitive to vemurafenib, and P-ERK suppression was not sustained in response to treatment. Although transient inhibition of phospho-ERK by vemurafenib was observed in CRC, rapid ERK re-activation occurred through EGFR-mediated activation of RAS and CRAF. BRAF mutant CRCs expressed higher levels of phospho-EGFR than BRAF mutant melanomas, suggesting that CRCs are specifically poised for EGFR-mediated resistance. Combined RAF and EGFR inhibition blocked reactivation of MAPK signaling in BRAF mutant CRC cells and markedly improved efficacy in vitro and in vivo. These findings support evaluation of combined RAF and EGFR inhibition in BRAF mutant CRC patients.