Crudden Caitrin, Ilic Marina, Suleymanova Naida, Worrall Claire, Girnita Ada, Girnita Leonard
Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and Karolinska University Hospital, 17176 Stockholm, Sweden.
Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and Karolinska University Hospital, 17176 Stockholm, Sweden; Dermatology Department, Karolinska University Hospital, Stockholm, Sweden.
Growth Horm IGF Res. 2015 Feb;25(1):2-12. doi: 10.1016/j.ghir.2014.10.002. Epub 2014 Oct 28.
The prime position of the insulin-like growth factor 1 receptor (IGF-1R), at the head of the principle mitogenic and anti-apoptotic signalling cascades, along with the resilience to transformation of IGF-1R deficient cells fuelled great excitement for its anti-cancer targeting. Yet its potential has not been fulfilled, as clinical trial results fell far short of expectations. Advancements in understanding of other receptors' function have now begun to shed light on this incongruity, with the now apparent parallels highlighting the immaturity of our understanding of IGF-1R biology, with the model used for drug development now recognised as having been too simplistic. Gathering together the many advancements of the field of IGF-1R research over the past decade, alongside those in the GPCR field, advocates for a major paradigm shift in our appreciation of the subtle workings of this receptor. This review will emphasise the updating of the IGF-1R's classification from an RTK, to an RTK/GPCR functional hybrid, which integrates both canonical kinase signalling with many functions characteristic of a GPCR. Recognition of the shortcomings of IGF-1R inhibitor drug development programs and the models used not only allows us to reignite the initial interest in the IGF-1R as an anti-cancer therapeutic target, but also points to the possibility of biased ligand therapeutics, which together may hold a very powerful key to unlocking the true potential of IGF-1R modulation.
胰岛素样生长因子1受体（IGF-1R）处于主要的促有丝分裂和抗凋亡信号级联反应之首，加之IGF-1R缺陷细胞对转化具有抗性，这使得针对其进行抗癌靶向治疗备受关注。然而，其潜力尚未实现，因为临床试验结果远未达到预期。如今，对其他受体功能认识的进展开始揭示这种不一致性，目前明显的相似之处凸显了我们对IGF-1R生物学理解的不成熟，而用于药物开发的模型现在被认为过于简单。汇总过去十年IGF-1R研究领域以及GPCR领域的诸多进展，提倡在我们对该受体微妙作用机制的认识上进行重大范式转变。本综述将强调IGF-1R分类从受体酪氨酸激酶（RTK）更新为RTK/GPCR功能杂种，它整合了典型的激酶信号传导与许多GPCR特有的功能。认识到IGF-1R抑制剂药物开发计划及所用模型的缺点，不仅使我们能够重新燃起对IGF-1R作为抗癌治疗靶点的最初兴趣，还指出了偏向性配体疗法的可能性，这两者可能共同成为释放IGF-1R调节真正潜力的关键。
