Bill Anke, Gutierrez Abraham, Kulkarni Sucheta, Kemp Carolyn, Bonenfant Debora, Voshol Hans, Duvvuri Umamaheswar, Gaither L Alex
Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
University of Pittsburgh, Medical Center, Department of Otolaryngology, Pittsburgh, PA 15213, USA.
Oncotarget. 2015 Apr 20;6(11):9173-88. doi: 10.18632/oncotarget.3277.
The epidermal growth factor receptor (EGFR) contributes to the pathogenesis of head&neck squamous cell carcinoma (HNSCC). However, only a subset of HNSCC patients benefit from anti-EGFR targeted therapy. By performing an unbiased proteomics screen, we found that the calcium-activated chloride channel ANO1 interacts with EGFR and facilitates EGFR-signaling in HNSCC. Using structural mutants of EGFR and ANO1 we identified the trans/juxtamembrane domain of EGFR to be critical for the interaction with ANO1. Our results show that ANO1 and EGFR form a functional complex that jointly regulates HNSCC cell proliferation. Expression of ANO1 affected EGFR stability, while EGFR-signaling elevated ANO1 protein levels, establishing a functional and regulatory link between ANO1 and EGFR. Co-inhibition of EGFR and ANO1 had an additive effect on HNSCC cell proliferation, suggesting that co-targeting of ANO1 and EGFR could enhance the clinical potential of EGFR-targeted therapy in HNSCC and might circumvent the development of resistance to single agent therapy. HNSCC cell lines with amplification and high expression of ANO1 showed enhanced sensitivity to Gefitinib, suggesting ANO1 overexpression as a predictive marker for the response to EGFR-targeting agents in HNSCC therapy. Taken together, our results introduce ANO1 as a promising target and/or biomarker for EGFR-directed therapy in HNSCC.
表皮生长因子受体（EGFR）在头颈部鳞状细胞癌（HNSCC）的发病机制中起作用。然而，只有一部分HNSCC患者能从抗EGFR靶向治疗中获益。通过进行无偏向性蛋白质组学筛选，我们发现钙激活氯离子通道ANO1与EGFR相互作用，并促进HNSCC中的EGFR信号传导。利用EGFR和ANO1的结构突变体，我们确定EGFR的跨膜/近膜结构域对于与ANO1的相互作用至关重要。我们的结果表明，ANO1和EGFR形成一个功能复合物，共同调节HNSCC细胞增殖。ANO1的表达影响EGFR稳定性，而EGFR信号传导提高ANO1蛋白水平，从而在ANO1和EGFR之间建立了功能和调节联系。EGFR和ANO1的共同抑制对HNSCC细胞增殖具有累加效应，这表明共同靶向ANO1和EGFR可增强EGFR靶向治疗在HNSCC中的临床潜力，并可能规避对单药治疗耐药性的产生。ANO1扩增和高表达的HNSCC细胞系对吉非替尼表现出增强的敏感性，这表明ANO1过表达可作为HNSCC治疗中对EGFR靶向药物反应的预测标志物。综上所述，我们的结果表明ANO1是HNSCC中EGFR导向治疗的一个有前景的靶点和/或生物标志物。
