General Medical Oncology, University Hospital Gasthuisberg, Leuven, Belgium.
Int J Cancer. 2013 Mar 1;132(5):1042-50. doi: 10.1002/ijc.27763. Epub 2012 Aug 28.
The epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of head and neck squamous cell carcinoma (HNSCC). Despite the high expression of EGFR in HNSCC, EGFR inhibitors have only limited success as monotherapy. The Grb2-associated binder (GAB) family of adaptor proteins acts as docking/scaffolding molecules downstream of tyrosine kinase receptors. We hypothesized that GAB1 may amplify EGFR-induced signaling in HNSCCs and therefore could play a role in the reduced sensitivity of HNSCC to EGFR inhibitors. We used representative human HNSCC cell lines overexpressing wild type EGFR, and expressing GAB1 but not GAB2. We demonstrated that baseline Akt and MAPK signaling were reduced in HNSCC cells in which GAB1 expression was reduced. Furthermore, the maximal EGF-induced activation of the Akt and MAPK pathway was reduced and delayed, and the duration of the EGF-induced activation of these pathways was reduced in cells with GAB1 knock-down. In agreement with this, HNSCC cells in which GAB1 levels were reduced showed an increased sensitivity to the EGFR inhibitor gefitinib. Our work demonstrates that GAB1 plays an important role as part of the mechanism of by which EGFR induces induced activation of the MAPK and AKT pathway. Our results identify GAB1 as an amplifier of the EGFR-initiated signaling, which may also interfere with EGFR degradation. These findings support the emerging notion that reducing GAB1 function may sensitize HNSCC to EGFR inhibitors, hence representing a new therapeutic target HNSCC treatment in combination with EGFR targeting agents.
表皮生长因子受体（EGFR）在头颈部鳞状细胞癌（HNSCC）的发病机制中起着重要作用。尽管 EGFR 在 HNSCC 中高表达，但 EGFR 抑制剂作为单一疗法仅取得有限的成功。Grb2 相关结合蛋白（GAB）家族的衔接蛋白作为酪氨酸激酶受体下游的对接/支架分子。我们假设 GAB1 可能放大 EGFR 在 HNSCC 中的诱导信号，因此可能在 HNSCC 对 EGFR 抑制剂的敏感性降低中发挥作用。我们使用表达野生型 EGFR 的代表性人 HNSCC 细胞系和表达 GAB1 但不表达 GAB2 的细胞系。我们证明，在 GAB1 表达降低的 HNSCC 细胞中，基线 Akt 和 MAPK 信号降低。此外，EGF 诱导的 Akt 和 MAPK 通路的最大激活被降低和延迟，并且在 GAB1 敲低的细胞中，EGF 诱导的这些通路的激活持续时间缩短。与此一致的是，GAB1 水平降低的 HNSCC 细胞对 EGFR 抑制剂吉非替尼的敏感性增加。我们的工作表明，GAB1 作为 EGFR 诱导 MAPK 和 AKT 通路激活的机制的一部分，起着重要作用。我们的结果表明，GAB1 是 EGFR 起始信号的放大器，它也可能干扰 EGFR 降解。这些发现支持这样一种观点，即降低 GAB1 功能可能使 HNSCC 对 EGFR 抑制剂敏感，因此代表了与 EGFR 靶向药物联合治疗 HNSCC 的新治疗靶点。
