Signaling via ErbB2 and ErbB3 associates with resistance and Epidermal Growth Factor Receptor (EGFR) amplification with sensitivity to EGFR inhibitor gefitinib in head and neck squamous cell carcinoma cells
Signaling via ErbB2 and ErbB3 associates with resistance and Epidermal Growth Factor Receptor (EGFR) amplification with sensitivity to EGFR inhibitor gefitinib in head and neck squamous cell carcinoma cells
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DOI：
10.1158/1078-0432.ccr-05-2404
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发表时间：
2006-07-01
影响因子：
11.5
通讯作者：
Elenius, Klaus
中科院分区：
文献类型：
--
作者：
Erjala, Kaisa;Sundvall, Maria;Elenius, Klaus
目的：表皮生长因子受体（EGFR）抑制剂吉非替尼（易瑞沙）已在针对癌症（如非小细胞肺癌和头颈部鳞状细胞癌（HNSCC））的临床试验中显示出抗肿瘤活性。对非小细胞肺癌的研究已经阐明了可能预测吉非替尼反应的因素。较少是已知的分子标志物，可以预测响应吉非替尼在HNSCC patients.Experimental Design：我们分析了可能的协会的反应，吉非替尼与EGFR/ErbB受体家族信号通路的分子标志物，使用10个建立HNSCC线在体外。使用克隆形成存活测定法测定吉非替尼敏感性的IC 50。通过EGFR、ErbB 2、ErbB 3和ErbB 4表达水平的Western和实时逆转录PCR分析以及pEGFR、pErbB 2、pErbB 3、pAkt和pErk的磷酸化分析评估ErbB信号传导。分别通过cDNA测序和实时定量PCR测定EGFR激酶结构域编码序列和EGFR基因拷贝数。结果：pErbB 2（P=0.02）和总ErbB 3蛋白（P = 0.02）表达水平与吉非替尼耐药相关。吉非替尼与帕妥珠单抗（Omnitarg）（一种靶向ErbB 2异源二聚化的抗体）组合，在相对吉非替尼耐药的HNSCC细胞系上提供了超过单独吉非替尼的额外生长抑制作用。相同的标记物不能预测西妥昔单抗的耐药性。相比之下，在吉非替尼（P=0.0498）和西妥昔单抗（P=0.053）中观察到EGFR基因拷贝数与药物敏感性之间存在相似的趋势。结论：EGFR扩增可预测HNSCC对吉非替尼的敏感性。然而，EGFR以外的其他EGFR/ErbB受体家族成员可能导致吉非替尼耐药。ErbB 2和ErbB 3可能作为吉非替尼联合治疗HNSCC的预测标志物和治疗靶点。
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.