PURPOSE:The epidermal growth factor receptor (EGFR) inhibitor gefitinib (Iressa) has shown antitumor activity in clinical trials against cancers, such as non-small cell lung cancer and head and neck squamous cell carcinoma (HNSCC). Research on non-small cell lung cancer has elucidated factors that may predict response to gefitinib. Less is known about molecular markers that may predict response to gefitinib in HNSCC patients. EXPERIMENTAL DESIGN:We analyzed possible associations of responsiveness to gefitinib with molecular markers of the EGFR/ErbB receptor family signaling pathway using 10 established HNSCC lines in vitro. IC50 of gefitinib sensitivity was determined using clonogenic survival assays. ErbB signaling was assessed by Western and real-time reverse transcription-PCR analyses of EGFR, ErbB2, ErbB3, and ErbB4 expression levels as well as by phosphorylation analysis of pEGFR, pErbB2, pErbB3, pAkt, and pErk. EGFR sequences encoding kinase domain and EGFR gene copy numbers were determined by cDNA sequencing and real-time PCR, respectively. Finally, responsiveness to gefitinib was compared with responsiveness to the anti-EGFR antibody cetuximab (Erbitux). RESULTS:Expression levels of pErbB2 (P = 0.02) and total ErbB3 protein (P = 0.02) associated with resistance to gefitinib. Combining gefitinib with pertuzumab (Omnitarg), an antibody targeting ErbB2 heterodimerization, provided additional growth-inhibitory effect over gefitinib alone on relatively gefitinib-resistant HNSCC cell lines. The same markers did not predict resistance to cetuximab. In contrast, a similar trend suggesting association between EGFR gene copy number and drug sensitivity was observed for both gefitinib (P = 0.0498) and cetuximab (P = 0.053). No activating EGFR mutations were identified. CONCLUSIONS:EGFR amplification may predict sensitivity to gefitinib in HNSCC. However, other EGFR/ErbB receptor family members than EGFR may contribute to resistance to gefitinib. ErbB2 and ErbB3 may have potential as predictive markers and as therapeutic targets for combination therapy in treatment of HNSCC with gefitinib.

译文

用途:表皮生长因子受体(EGFR)抑制剂吉非替尼(Iressa)在针对癌症的临床试验中显示出抗肿瘤活性,例如非小细胞肺癌和头颈鳞状细胞癌(HNSCC)。对非小细胞肺癌的研究阐明了可能预测对吉非替尼反应的因素。关于可能预测HNSCC患者对吉非替尼反应的分子标志物知之甚少。
实验设计:我们使用10条已建立的HNSCC细胞系,分析了对吉非替尼反应性与EGFR / ErbB受体家族信号传导途径的分子标记物之间的可能联系。吉非替尼敏感性的IC50使用克隆发生生存测定法确定。通过对EGFR,ErbB2,ErbB3和ErbB4表达水平的Western和实时逆转录PCR分析以及对pEGFR,pErbB2,pErbB3,pAkt和pErk的磷酸化分析,评估了ErbB信号传导。分别通过cDNA测序和实时PCR确定编码激酶结构域的EGFR序列和EGFR基因拷贝数。最后,将对吉非替尼的反应性与对抗EGFR抗体西妥昔单抗(Erbitux)的反应性进行了比较。
结果:与吉非替尼耐药相关的pErbB2(P = 0.02)和总ErbB3蛋白(P = 0.02)的表达水平。吉非替尼与靶向ErbB2异二聚化的抗体pertuzumab(Omnitarg)的组合,在相对耐吉非替尼的HNSCC细胞系上提供了比单独吉非替尼更高的生长抑制作用。相同的标记不能预测对西妥昔单抗的耐药性。相反,吉非替尼(P = 0.0498)和西妥昔单抗(P = 0.053)观察到相似的趋势,表明EGFR基因拷贝数与药物敏感性之间存在关联。未鉴定出激活的EGFR突变。
结论:EGFR扩增可能预示了HNSCC对吉非替尼的敏感性。但是,除EGFR外,其他EGFR / ErbB受体家族成员可能会导致对吉非替尼的耐药性。 ErbB2和ErbB3可能具有作为吉非替尼治疗HNSCC的联合治疗的预测标志物和治疗靶标的潜力。

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