UO di Oncologia Medica, Fondazione Poliambulanza, Via Bissolati 54, 25124 Brescia, Italy.
Curr Drug Targets. 2009 Oct;10(10):1033-40. doi: 10.2174/138945009789577891.
The anti-epidermal growth factor receptor monoclonal antibodies cetuximab and panitumumab have established efficacy as single agent and in combination with chemotherapy in advanced colorectal cancer. However, only a small percentage of unselected patients (around 10%) are responsive to these costly agents. Mutations in the KRAS gene are associated with resistance to both cetuximab and panitumumab and account for approximately 30% to 40% of resistant patients. Nevertheless, having an intact KRAS is necessary but not sufficient to derive benefit from EGFR inhibition. Further, positive predictive markers that are currently being evaluated include an increase in EGFR gene copy number and additional data suggest that other EGFR downstream pathways such as the PI3K/PTEN/AKT/mTOR and JAK/STAT pathways are also important when considering mechanisms of EGFR antibody resistance. New data seem to support the role of BRAF mutational status. In addition, high mRNA levels of the EGFR-ligands Epiregulin and Amphiregulin have been associated with increased responsiveness to cetuximab. In this article we will review the available clinical and experimental data potentially useful for a better patients' selection.
抗表皮生长因子受体单克隆抗体西妥昔单抗和帕尼单抗已被证实可单药或联合化疗用于治疗晚期结直肠癌。然而，只有一小部分未经选择的患者（约 10%）对这些昂贵的药物有反应。KRAS 基因突变与西妥昔单抗和帕尼单抗的耐药性相关，约占耐药患者的 30%至 40%。然而，KRAS 基因完整是从 EGFR 抑制中获益的必要但非充分条件。此外，目前正在评估的阳性预测标志物包括 EGFR 基因拷贝数增加，并且其他数据表明，在考虑 EGFR 抗体耐药机制时，其他 EGFR 下游途径，如 PI3K/PTEN/AKT/mTOR 和 JAK/STAT 途径也很重要。新的数据似乎支持 BRAF 突变状态的作用。此外，EGFR 配体 Epiregulin 和 Amphiregulin 的高 mRNA 水平与对西妥昔单抗的反应性增加有关。本文将综述现有临床和实验数据，这些数据可能有助于更好地选择患者。
