Dual targeting of the insulin-like growth factor and collateral pathways in cancer: combating drug resistance.
Dual targeting of the insulin-like growth factor and collateral pathways in cancer: combating drug resistance.
复制标题
癌症中胰岛素样生长因子和附带途径的双重靶向：对抗耐药性。
DOI：
10.3390/cancers3033029
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发表时间：
2011-07-26
期刊：
影响因子：
5.2
通讯作者：
Benjamin R
中科院分区：
文献类型：
--
作者：
Ludwig JA;Lamhamedi-Cherradi SE;Lee HY;Naing A;Benjamin R
胰岛素样生长因子途径由生长因子、同源受体和结合蛋白的复杂相互作用调节，对于癌症的许多特征（例如肿瘤发生、细胞分裂、生长和抗肿瘤耐药性）至关重要。当然，许多临床试验都试图直接消除胰岛素样生长因子受体 1 (IGF-1R) 功能和/或间接减轻其下游介质，如 mTOR、PI3K、MAPK 等，假设此类治疗干预措施将提供临床益处，这可以通过肿瘤生长受损以及延长患者无进展生存期和总生存期来证明。尽管参加 I 期或 II 期临床试验的一小部分患者显示出对 IGF-1R 靶向治疗的显着临床反应（大多数使用 IGF-1R 单克隆抗体），但总体而言，抗癌效果并不令人印象深刻且不可持续，因为即使是那些具有显着临床反应的患者，当单独使用时，通过尚未确定的机制，似乎也会迅速获得对 IGF-1R 靶向药物的耐药性。由于 IGF-1R 受体只是汇聚常见细胞内信号级联的众多受体之一，因此有效的 IGF-1R 靶向很可能必须与冗余信号通路的阻断同时发生。在此，我们提出了将 IGF-1R 和其他信号分子双重靶向作为对抗癌和肉瘤获得性耐药性的有效策略的基本原理。
The insulin-like growth factor pathway, regulated by a complex interplay of growth factors, cognate receptors, and binding proteins, is critically important for many of the hallmarks of cancer such as oncogenesis, cell division, growth, and antineoplastic resistance. Naturally, a number of clinical trials have sought to directly abrogate insulin-like growth factor receptor 1 (IGF-1R) function and/or indirectly mitigate its downstream mediators such as mTOR, PI3K, MAPK, and others under the assumption that such therapeutic interventions would provide clinical benefit, demonstrable by impaired tumor growth as well as prolonged progression-free and overall survival for patients. Though a small subset of patients enrolled within phase I or II clinical trials revealed dramatic clinical response to IGF-1R targeted therapies (most using monoclonal antibodies to IGF-1R), in toto, the anticancer effect has been underwhelming and unsustained, as even those with marked clinical responses seem to rapidly acquire resistance to IGF-1R targeted agents when used alone through yet to be identified mechanisms. As the IGF-1R receptor is just one of many that converge upon common intracellular signaling cascades, it is likely that effective IGF-1R targeting must occur in parallel with blockade of redundant signaling paths. Herein, we present the rationale for dual targeting of IGF-1R and other signaling molecules as an effective strategy to combat acquired drug resistance by carcinomas and sarcomas.