Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies
Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies
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DOI：
10.1158/0008-5472.can-06-4158
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发表时间：
2007-03-15
期刊：
影响因子：
11.2
通讯作者：
Bardelli, Alberto
中科院分区：
文献类型：
--
作者：
Benvenuti, Silvia;Sartore-Bianchi, Andrea;Bardelli, Alberto
针对表皮生长因子受体（EGFR）细胞外结构域的单克隆抗体（mab）已被引入治疗转移性结直肠癌（mCRC）。我们最近报道了EGFR拷贝数的增加可以预测对抗EGFR单克隆抗体的反应，并且可以根据EGFR拷贝数选择患者进行治疗。在这里，我们发现激活RAS/RAF信号通路的突变也是mCRC患者的预测和预后指标，与抗egfr单克隆抗体的反应呈负相关。在CRCs细胞模型中，通过引入活化的K-RAS等位基因（Gly(12)Val）激活RAS信号通路会损害抗egfr单克隆抗体的治疗效果。在携带组成型活性RAS的癌细胞中，对丝裂原活化蛋白激酶（MAPK）信号级联的药理学抑制改善了基于单克隆抗体的抗egfr治疗。这些结果对识别可能对抗egfr治疗有反应的患者具有重要意义。它们还提供了联合治疗的基本原理，同时针对结直肠癌患者的EGFR和RAS/RAF/MAPK信号通路。
Monoclonal antibodies (mAbs) against the extracellular domain of the epidermal growth factor receptor (EGFR) have been introduced for the treatment of metastatic colorectal cancer (mCRC). We have reported recently that increased copy number of the EGFR can predict response to anti-EGFR mAbs and that patients might be selected for treatment based on EGFR copy number. Here, we show that mutations activating the RAS/RAF signaling pathway are also predictive and prognostic indicators in mCRC patients, being inversely correlated with response to anti-EGFR mAbs. In cellular models of CRCs, activation of the RAS signaling pathway by introduction of an activated K-RAS allele (Gly(12)Val) impairs the therapeutic effect of anti-EGFR mAbs. In cancer cells carrying constitutively active RAS, the pharmacologic inhibition of the mitogen-activated protein kinase (MAPK) signaling cascade improves anti-EGFR treatment based on mAbs. These results have implications for the identification of patients who are likely to respon to anti-EGFR treatment. They also provide the rationale for combination therapies, targeted simultaneously to the EGFR and RAS/RAF/MAPK signaling pathways in CRC patients.