Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Lancet Oncol. 2013 Jul;14(8):e302-9. doi: 10.1016/S1470-2045(13)70085-8.
Cancers of the head and neck that arise from habitual exposure to carcinogens have lower cure rates than those that arise from infection with human papillomavirus (HPV), and intensification of cytotoxic chemotherapy and radiation has not improved outcomes. HPV-negative head and neck cancers abundantly express EGFR, and the monoclonal antibody cetuximab, directed against EGFR, is the only targeted therapy that has improved disease survival so far. However, response rates to single-agent cetuximab are lower than 15%, and cetuximab given with chemotherapy or radiation leads to only a modest effect on survival. Thus, investigating the mechanisms of resistance to EGFR inhibition in HPV-negative head and neck cancer might help identify novel and active therapies. In this Review, we focus on therapies in development that target redundant receptor tyrosine kinases (eg, HER2 and MET), reduce or abrogate nuclear functions of EGFR, affect cellular trafficking by inhibition of histone deacetylase, or treatments that might address resistance that arises in the EGFR signalling stream (eg, aurora-kinase inhibitors and STAT decoys).
与 HPV 感染相关的头颈部癌症的治愈率高于因习惯性暴露于致癌物质而导致的头颈部癌症，而且细胞毒性化疗和放疗的强化并没有改善结果。HPV 阴性的头颈部癌症大量表达 EGFR，针对 EGFR 的单克隆抗体西妥昔单抗是迄今为止唯一改善疾病生存的靶向治疗药物。然而，单一药物西妥昔单抗的反应率低于 15%，并且与化疗或放疗联合使用西妥昔单抗对生存的影响也只是适度的。因此，研究 HPV 阴性头颈部癌中 EGFR 抑制的耐药机制可能有助于确定新的有效的治疗方法。在这篇综述中，我们重点介绍了正在开发中的针对冗余受体酪氨酸激酶（例如 HER2 和 MET）的治疗方法、降低或消除 EGFR 核功能的方法、通过抑制组蛋白去乙酰化酶影响细胞运输的方法，或者可能解决 EGFR 信号通路中出现的耐药性的治疗方法（例如，极光激酶抑制剂和 STAT 诱饵）。
