Translational Research, OSI Pharmaceuticals, Farmingdale, NY 11735, USA.
Expert Opin Investig Drugs. 2011 May;20(5):605-21. doi: 10.1517/13543784.2011.558501. Epub 2011 Mar 30.
The IGF-1 receptor (IGF-1R) is a receptor tyrosine kinase and is well established as a key regulator of tumor cell growth and survival. There is also a growing body of data to support a role for the structurally and functionally related insulin receptor (IR) in human cancer. Bidirectional crosstalk between IGF-1R and IR is observed, where specific inhibition of either receptor confers a compensatory increase in the activity for the reciprocal receptor, therefore dual inhibition of both IGF-1R and IR may be important for optimal efficacy. The importance of IGF-1R and IR as targets in cancer is further underscored by their contribution to resistance against both cytotoxic and molecularly targeted anti-cancer therapeutics. Currently, both IGF-1R-neutralizing antibodies and small-molecule tyrosine kinase inhibitors of IGF-1R/IR are in clinical development.
The importance of IGF-1R and IR as cancer targets and how IGF-1R/IR inhibitors may sensitize tumor cells to the anti-proliferative and pro-apoptotic effects of other anti-tumor agents. The potential advantages of small molecule IGF-1R/IR inhibitors compared with IGF-1R-specific neutralizing antibodies, and the characteristics of small-molecule IGF-1R inhibitors that have entered clinical development.
Because of compensatory crosstalk between IGF-1R and IR, dual IGF-1R and IR tyrosine kinase inhibitors may have superior anti-tumor activity compared to anti-IGF-1R specific antibodies. The clinical success for IGF-1R/IR inhibitors may ultimately be dependent upon our ability to correctly administer these agents to the right niche patient subpopulation using single agent therapy, when appropriate, or using the right combination therapy.
胰岛素样生长因子 1 受体(IGF-1R)是一种受体酪氨酸激酶,它是肿瘤细胞生长和存活的关键调节因子,这一点已得到充分证实。越来越多的数据也支持结构和功能相关的胰岛素受体(IR)在人类癌症中的作用。IGF-1R 和 IR 之间存在双向串扰,即对任一受体的特异性抑制会导致其互补受体的活性代偿性增加,因此,双重抑制 IGF-1R 和 IR 可能对最佳疗效很重要。IGF-1R 和 IR 作为癌症靶点的重要性,进一步体现在它们对细胞毒性和分子靶向抗癌治疗的耐药性的贡献上。目前,IGF-1R 中和抗体和 IGF-1R/IR 的小分子酪氨酸激酶抑制剂都处于临床开发阶段。
IGF-1R 和 IR 作为癌症靶点的重要性,以及 IGF-1R/IR 抑制剂如何使肿瘤细胞对其他抗肿瘤药物的抗增殖和促凋亡作用敏感。与 IGF-1R 特异性中和抗体相比,小分子 IGF-1R/IR 抑制剂的潜在优势,以及已进入临床开发的小分子 IGF-1R 抑制剂的特征。
由于 IGF-1R 和 IR 之间存在代偿性串扰,双重 IGF-1R 和 IR 酪氨酸激酶抑制剂可能比针对 IGF-1R 的特异性抗体具有更好的抗肿瘤活性。IGF-1R/IR 抑制剂的临床成功最终可能取决于我们能否正确地将这些药物用于合适的亚群患者,无论是单独使用,还是使用合适的联合治疗。