Normanno Nicola, Tejpar Sabine, Morgillo Floriana, De Luca Antonella, Van Cutsem Eric, Ciardiello Fortunato
Cell Biology and Biotherapy Unit, INT-Fondazione Pascale, Naples, Italy.
Nat Rev Clin Oncol. 2009 Sep;6(9):519-27. doi: 10.1038/nrclinonc.2009.111. Epub 2009 Jul 28.
EGFR regulates cancer-cell proliferation, apoptosis and tumor-induced neoangiogenesis, and has been validated as a relevant therapeutic target in several human cancers, including metastatic colorectal cancer (mCRC). The anti-EGFR monoclonal antibodies cetuximab and panitumumab are available for the treatment of patients with mCRC. Although EGFR is expressed in approximately 85% of patients with mCRC, the clinical efficacy of treatment with anti-EGFR antibodies is limited to a subset of patients. A series of potential biomarkers that could be useful in predicting response to EGFR inhibitors has been investigated. In patients with mCRC, activating mutations within KRAS can predict resistance to anti-EGFR monoclonal antibodies. Activating mutations in KRAS, which could result in EGFR-independent intracellular signal transduction activation, are found in approximately 35-40% of patients with mCRC. These mutations are almost exclusively detected in codons 12 and 13 of exon 2. KRAS mutations have been significantly associated with lack of response to cetuximab or panitumumab therapy in patients with mCRC, which suggests that EGFR-independent, constitutive activation of the RAS signaling pathway could impair response to anti-EGFR drugs. We summarize the experimental and clinical evidence supporting the use of KRAS testing for the optimal selection of patients with mCRC to be treated with anti-EGFR monoclonal antibodies.
表皮生长因子受体（EGFR）调控癌细胞的增殖、凋亡以及肿瘤诱导的新生血管生成，并且已被证实是包括转移性结直肠癌（mCRC）在内的多种人类癌症的相关治疗靶点。抗EGFR单克隆抗体西妥昔单抗和帕尼单抗可用于治疗mCRC患者。尽管约85%的mCRC患者表达EGFR，但抗EGFR抗体治疗的临床疗效仅限于一部分患者。一系列可能有助于预测对EGFR抑制剂反应的潜在生物标志物已被研究。在mCRC患者中，KRAS基因内的激活突变可预测对抗EGFR单克隆抗体的耐药性。约35%-40%的mCRC患者存在KRAS激活突变，这可能导致不依赖EGFR的细胞内信号转导激活。这些突变几乎只在第2外显子的12和13密码子中检测到。KRAS突变与mCRC患者对西妥昔单抗或帕尼单抗治疗无反应显著相关，这表明RAS信号通路的不依赖EGFR的组成性激活可能会削弱对抗EGFR药物的反应。我们总结了支持使用KRAS检测来优化选择接受抗EGFR单克隆抗体治疗的mCRC患者的实验和临床证据。
