Department of Pharmacology, Physiology, & Neuroscience, Center for Cell Signaling and Cancer Institute of New Jersey, Rutgers Biomedical and Health Sciences, Newark, New Jersey, United States.
Endocr Relat Cancer. 2023 Aug 25;30(10). doi: 10.1530/ERC-23-0031. Print 2023 Oct 1.
Despite decades of research presenting insulin-like growth factor-1 receptor (IGF1R) as an attractive target for cancer therapy, IGF1R inhibitors ultimately failed in clinical trials. This was surprising due to the known cancer-promoting functions of IGF1R, including stimulation of cell invasion, proliferation, and survival. Discourse in the literature has acknowledged that a lack of patient stratification may have impacted the success of IGF1R-inhibitor trials. This argument alludes to the possibility that IGF1R function may be contingent on tumor type and cellular composition. Looking into the known roles of IGF1R, it becomes clear that this receptor interacts with a multitude of different proteins and even has tumor-suppressing functions. IGF1R is implicated in both cell-cell and cell-surface adhesion dynamics, and the effects of either IGF1R downregulation or pharmacological inhibition on cellular adhesion remain poorly understood. In turn, adhesion receptors modulate IGF1R signaling. In addition, our understanding of IGF1R function in tumor-associated immune and stromal cells is lacking, which could contribute to the overwhelming failure of IGF1R inhibitors in the clinic. In this review, we re-investigate clinical trial data to make connections between the failure of these drugs in human cancer patients and the understudied facets of IGF1R function. We describe lesser-known and potentially tumor-suppressive functions of IGF1R that include promoting cell-cell adhesion through E-cadherin, augmenting a pro-inflammatory macrophage phenotype, and stimulating B cells to produce immunoglobulins. We also highlight the important role of adhesion receptors in regulating IGF1R function, and we use this information to infer stratification criteria for selecting patients that might benefit from IGF1R inhibitors.
尽管数十年来的研究表明胰岛素样生长因子-1 受体（IGF1R）是癌症治疗的一个有吸引力的靶点，但 IGF1R 抑制剂最终在临床试验中失败。这令人惊讶，因为 IGF1R 的已知促癌功能包括刺激细胞侵袭、增殖和存活。文献中的讨论承认，缺乏患者分层可能影响了 IGF1R 抑制剂试验的成功。这一论点暗示 IGF1R 的功能可能取决于肿瘤类型和细胞组成。深入研究 IGF1R 的已知作用，就会清楚地发现，这种受体与许多不同的蛋白质相互作用，甚至具有肿瘤抑制功能。IGF1R 参与细胞-细胞和细胞表面黏附动力学，IGF1R 下调或药物抑制对细胞黏附的影响仍知之甚少。反过来，黏附受体调节 IGF1R 信号。此外，我们对 IGF1R 在肿瘤相关免疫和基质细胞中的功能的理解也很缺乏，这可能导致 IGF1R 抑制剂在临床上的压倒性失败。在这篇综述中，我们重新研究了临床试验数据，以在这些药物在人类癌症患者中的失败与 IGF1R 功能的研究不足之间建立联系。我们描述了 IGF1R 不太为人知的、潜在的肿瘤抑制功能，包括通过 E-钙黏蛋白促进细胞-细胞黏附、增强促炎巨噬细胞表型以及刺激 B 细胞产生免疫球蛋白。我们还强调了黏附受体在调节 IGF1R 功能方面的重要作用，并利用这些信息推断出选择可能受益于 IGF1R 抑制剂的患者的分层标准。
