Ligand-Independent EGFR Activation by Anchorage-Stimulated Src Promotes Cancer Cell Proliferation and Cetuximab Resistance via ErbB3 Phosphorylation
Ligand-Independent EGFR Activation by Anchorage-Stimulated Src Promotes Cancer Cell Proliferation and Cetuximab Resistance via ErbB3 Phosphorylation
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DOI：
10.3390/cancers11101552
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发表时间：
2019-10-01
期刊：
影响因子：
5.2
通讯作者：
Ohnishi, Yuichi
中科院分区：
文献类型：
--
作者：
Nozaki, Masami;Yasui, Hiroki;Ohnishi, Yuichi
表皮生长因子受体(EGFR)通路的激活在癌症的进展中起着重要作用，并与患者预后不良有关。显示EGFR胞外区特异性结合的单抗西妥昔单抗已被证明在治疗局部晚期疾病和复发/转移性疾病方面有效。然而，西妥昔单抗的作用弱于EGFR酪氨酸激酶抑制剂(TKIs)。本研究以口腔鳞状细胞癌(OSCC)细胞株为研究对象，从分子水平探讨西妥昔单抗和EGFR TKI AG1478对细胞生长的影响差异。首先，我们发现存在EGFR抑制剂敏感(EIS)和EGFR抑制剂耐药细胞系。EIS细胞株不仅表达EGFR，而且表达ErbB3，两者都明显被磷酸化。西妥昔单抗对磷酸化ErbB3水平无影响，但AG1478可降低ErbB3的磷酸化水平。EGFR配体处理增加了磷酸化的EGFR水平，但不增加磷酸化的ErbB3。此外，当只能依靠锚定生长的EIS细胞系悬浮生长时，细胞生长受到抑制，磷酸化粘着斑激酶(FAK)、Src和ErbB3的水平显著降低。FAK抑制剂PF573228不影响ErbB3的磷酸化水平，但可被Src抑制。最后，西妥昔单抗和Src抑制剂在抑制EIS细胞系生长方面产生了相加的作用。
Activation of the epidermal growth factor receptor (EGFR) pathway plays an important role in the progression of cancer and is associated with a poor prognosis in patients. The monoclonal antibody cetuximab, which displays EGFR extracellular domain-specific binding, has proven effective in the treatment of locally advanced disease and relapsed/metastatic disease. However, the effects of cetuximab are weaker than those of EGFR tyrosine kinase inhibitors (TKIs). This study investigates differences in the effects on cell growth of cetuximab and EGFR TKI AG1478 at the molecular level using oral squamous cell carcinoma (OSCC) cell lines. First, we found that there were EGFR-inhibitor-sensitive (EIS) and EGFR-inhibitor-resistant cell lines. The EIS cell lines expressed not only EGFR but also ErbB3, and both were clearly phosphorylated. The levels of phosphorylated ErbB3 were unaffected by cetuximab but were reduced by AG1478. EGFR ligand treatment increased the levels of phosphorylated EGFR but not phosphorylated ErbB3. Moreover, when EIS cell lines that were only capable of anchorage-dependent growth were grown in suspension, cell growth was suppressed and the levels of phosphorylated focal adhesion kinase (FAK), Src, and ErbB3 were significantly reduced. The levels of phosphorylated ErbB3 were unaffected by the FAK inhibitor PF573228, but were reduced by Src inhibition. Finally, combining cetuximab and a Src inhibitor produced an additive effect on the inhibition of EIS cell line growth.