Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
Endocrinology. 2021 Oct 1;162(10). doi: 10.1210/endocr/bqab147.
Type 1 insulin-like growth factor receptor (IGF-1R) is a transmembrane tyrosine kinase receptor and a mediator of the biologic effects of insulin-like growth factor (IGF)-I and -II. Inhibitors of IGF-1R signaling were tested in clinical cancer trials aiming to assess the utility of this receptor as a therapeutic target; essentially all IGF-1R inhibitors failed to provide an additional benefit compared with standard-of-care therapy. In this review, we will evaluate the role the insulin receptor (IR) plays in mediating IGF signaling and subsequent metabolic and mitogenic effects as 1 possible reason for these failures. IR is expressed as 2 isoforms, with the fetal isoform IR-A derived from alternative splicing and loss of exon 11, the adult isoform (IR-B) includes this exon. Cancer frequently re-expresses fetal proteins and this appears to be the case in cancer with a re-expression of the fetal isoform and an increased IR-A:IR-B ratio. The biological effects of IR isoform signaling are complex and not completely understood although it has been suggested that IR-A could stimulate mitogenic signaling pathways, play a role in cancer cell stemness, and mediate tolerance to cancer therapies. From a clinical perspective, the IR-A overexpression in cancer may explain why targeting IGF-1R alone was not successful. However, given the predominance of IR-A expression in cancer, it may also be possible to develop isoform specific inhibitors and avoid the metabolic consequences of inhibiting IR-B. If such inhibitors could be developed, then IR-A expression could serve as a predictive biomarker, and cotargeting IR-A and IGF-1R could provide a novel, more effective therapy method.
1 型胰岛素样生长因子受体（IGF-1R）是一种跨膜酪氨酸激酶受体，也是胰岛素样生长因子（IGF）-I 和 -II 生物效应的介质。在旨在评估该受体作为治疗靶点的实用性的临床癌症试验中测试了 IGF-1R 信号通路抑制剂；基本上，与标准治疗相比，所有 IGF-1R 抑制剂都未能提供额外的益处。在这篇综述中，我们将评估胰岛素受体（IR）在介导 IGF 信号转导以及随后的代谢和促有丝分裂效应中所起的作用，这可能是这些失败的原因之一。IR 有 2 种异构体表达，其中来自选择性剪接和缺失外显子 11 的胎儿异构体 IR-A，成人异构体（IR-B）包括该外显子。癌症经常重新表达胎儿蛋白，在癌症中似乎也是如此，即重新表达胎儿异构体和增加 IR-A:IR-B 比值。IR 同工型信号的生物学效应是复杂的，尚未完全理解，尽管有人提出 IR-A 可以刺激促有丝分裂信号通路，在癌细胞干性中发挥作用，并介导对癌症治疗的耐受性。从临床角度来看，癌症中 IR-A 的过表达可能解释了为什么单独靶向 IGF-1R 不成功。然而，鉴于 IR-A 在癌症中的表达优势，也有可能开发同工型特异性抑制剂并避免抑制 IR-B 的代谢后果。如果能够开发出这样的抑制剂，那么 IR-A 的表达可以作为预测生物标志物，并且同时靶向 IR-A 和 IGF-1R 可以提供一种新的、更有效的治疗方法。
