Department of Therapeutic Radiology, Yale University, New Haven, Connecticut.
Department of Medicine, Yale School of Medicine, Yale University, New Haven, Connecticut.
Mol Cancer Ther. 2019 Nov;18(11):2124-2134. doi: 10.1158/1535-7163.MCT-19-0163. Epub 2019 Aug 6.
EGFR signaling confers resistance to radiotherapy and is a validated target in head and neck squamous cell carcinoma (HNSCC). The inhibition of EGFR in combination with radiotherapy improves local control and overall survival in these patients; however, therapeutic resistance limits the efficacy of this approach. We therefore sought to identify cellular mechanisms that cause resistance to EGFR inhibition and radiotherapy in HNSCC. Though clonal isolation of carcinoma cells exposed to increasing concentrations of cetuximab, we found that resistant cells upregulate prosurvival ErbB3 and AKT signaling. Using EFM-19 cells and confirmatory analysis of protein levels, we demonstrate that cetuximab resistance is characterized by enhanced neuregulin expression identifying a novel adaptive mechanism of therapeutic resistance. Inhibition of this autocrine loop with CDX-3379 (an ErbB3 specific antibody) was sufficient to block ErbB3/AKT signaling in cetuximab resistant cells. The combination of CDX-3379 and cetuximab reduced proliferation and survival after radiotherapy in several HNSCC cell lines. These findings were confirmed in xenograft tumor growth experiments including an approach using growth factor-supplemented Matrigel. , the delivery of EGFR and ErbB3 antibodies significantly reduced tumor growth in cetuximab-resistant FaDu and CAL27 xenografts. In summary, this work demonstrates that autocrine NRG ligand secretion is a mechanism for therapeutic resistance to cetuximab and radiotherapy. This cross-resistance to both therapeutic modalities identifies NRG as an actionable therapeutic target for improving treatment regimens in HNSCC.
表皮生长因子受体（EGFR）信号转导可导致头颈部鳞状细胞癌（HNSCC）对放疗产生抵抗，其已被验证为治疗靶点。在这些患者中，EGFR 抑制剂联合放疗可提高局部控制率和总体生存率；然而，治疗抵抗限制了这种方法的疗效。因此，我们试图确定导致 HNSCC 中 EGFR 抑制和放疗抵抗的细胞机制。通过对暴露于不断增加浓度西妥昔单抗的癌细胞进行克隆分离，我们发现耐药细胞上调了生存相关的 ErbB3 和 AKT 信号。通过使用 EFM-19 细胞和对蛋白水平的确认性分析，我们证明西妥昔单抗耐药的特征是神经调节蛋白表达增强，这确定了一种新的治疗抵抗适应性机制。用 CDX-3379（一种 ErbB3 特异性抗体）抑制这种自分泌环足以阻断西妥昔单抗耐药细胞中的 ErbB3/AKT 信号。CDX-3379 与西妥昔单抗联合应用可降低几种 HNSCC 细胞系在放疗后的增殖和存活。在包括使用生长因子补充的 Matrigel 的移植瘤生长实验中证实了这些发现。此外，EGFR 和 ErbB3 抗体的递送可显著减少西妥昔单抗耐药的 FaDu 和 CAL27 移植瘤的生长。总之，这项工作表明，自分泌 NRG 配体分泌是对西妥昔单抗和放疗产生治疗抵抗的一种机制。这种对两种治疗方式的交叉抵抗表明 NRG 是改善 HNSCC 治疗方案的可行治疗靶点。
