Center of Molecular Immunology Havana, Cuba ; Biotech Pharmaceuticals Co. Ltd. Beijing, China.
Front Pharmacol. 2013 Apr 26;4:53. doi: 10.3389/fphar.2013.00053. eCollection 2013.
Tumor cell growth and survival can often be impaired by inactivating a single oncogen- a phenomenon that has been called as "oncogene addiction." It is in such scenarios that molecular targeted therapies may succeed. among known oncogenes, the epidermal growth factor receptor (EGFR) has become the target of different cancer therapies. So far, however, the clinical benefit from EGFR-targeted therapies has been rather limited. a critical review of the large amount of clinical data obtained with anti-EGFR agents, carried out from the perspective of the oncogene addiction concept, may help to understand the causes of the unsatisfactory results. In this article we intend to do such an exercise taking as basis for the analysis a few case studies of anti-EGFR agents that are currently in the clinic. There, the "EGFR addiction" phenomenon becomes apparent in high-responder patients. We further discuss how the concept of oncogene addiction needs to be interpreted on the light of emerging experimental evidences and ideas; in particular, that EGFR addiction may reflect the interconnection of several cellular pathways. In this regard we set forth several hypotheses; namely, that requirement of higher glucose uptake by hypoxic tumor cells may reinforce EGFR addiction; and that chronic use of EGFR-targeted antibodies in EGFR-addicted tumors would induce stable disease by reversing the malignant phenotype of cancer stem cells and also by sustaining an anti-tumor T cell response. Finally, we discuss possible reasons for the failure of certain combinatorial therapies involving anti-EGFR agents, arguing that some of these agents might produce either a negative or a positive trans-modulation effect on other oncogenes. It becomes evident that we need operational definitions of EGFR addiction in order to determine which patient populations may benefit from treatment with anti-EGFR drugs, and to improve the design of these therapies.
肿瘤细胞的生长和存活通常可以通过失活单个致癌基因来实现，这种现象被称为“致癌基因成瘾”。正是在这种情况下，分子靶向治疗可能会取得成功。在已知的致癌基因中，表皮生长因子受体 (EGFR) 已成为不同癌症治疗的靶点。然而，到目前为止，EGFR 靶向治疗的临床获益相当有限。从“致癌基因成瘾”的角度对大量的临床数据进行批判性回顾，可能有助于了解结果不理想的原因。在本文中，我们打算从目前在临床上使用的几种抗 EGFR 药物的基础上，进行这样的分析。在这些药物中，“EGFR 成瘾”现象在高反应患者中变得明显。我们进一步讨论了如何根据新兴的实验证据和观点来解释致癌基因成瘾的概念；特别是，EGFR 成瘾可能反映了几个细胞途径的相互关联。在这方面，我们提出了几个假设；即，缺氧肿瘤细胞对更高葡萄糖摄取的需求可能会增强 EGFR 成瘾；并且，在 EGFR 成瘾肿瘤中慢性使用 EGFR 靶向抗体可能通过逆转癌症干细胞的恶性表型并维持抗肿瘤 T 细胞反应来诱导稳定的疾病。最后，我们讨论了某些包含抗 EGFR 药物的联合治疗失败的可能原因，认为其中一些药物可能对其他致癌基因产生负或正的反调节作用。显然，我们需要 EGFR 成瘾的操作定义，以确定哪些患者群体可能从抗 EGFR 药物治疗中获益，并改善这些治疗的设计。
