Suleymanova Naida, Crudden Caitrin, Worrall Claire, Dricu Anica, Girnita Ada, Girnita Leonard
Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Biochemistry Unit, University of Medicine and Pharmacy of Craiova, Craiova, Romania.
Oncotarget. 2017 Jul 17;8(47):82256-82267. doi: 10.18632/oncotarget.19286. eCollection 2017 Oct 10.
Due to its ability to compensate for signals lost following therapeutic MAPK-inhibition, insulin-like growth factor type 1 receptor (IGF-1R) co-targeting is a rational approach for melanoma treatment. However IGF-1R conformational changes associated with its inhibition can preferentially activate MAPK-pathway in a kinase-independent manner, through a process known as biased signaling. We explored the impact of biased IGF-1R signaling, on response to MAPK inhibition in a panel of skin melanoma cell lines with differing MAPK and p53 mutation statuses. Specific siRNA towards IGF-1R down-regulates the receptor and all its signaling in a balanced manner, whilst IGF-1R targeting by small molecule Nutlin-3 parallels receptor degradation with a transient biased pERK1/2 activity, with both strategies synergizing with MEK1/2 inhibition. On the other hand, IGF-1R down-regulation by a targeted antibody (Figitumumab) induces a biased receptor conformation, preserved even when the receptor is exposed to the balanced natural ligand IGF-1. This process sustains MAPK activity and competes with the MEK1/2 inhibition. Our results indicate that IGF-1R down-regulation offers an approach to increase the sensitivity of melanoma cells to MAPK inhibition, and highlights that controlling biased signaling could provide greater specificity and precision required for multi-hit therapy.
由于胰岛素样生长因子1型受体（IGF-1R）能够补偿治疗性MAPK抑制后丢失的信号，因此联合靶向IGF-1R是一种合理的黑色素瘤治疗方法。然而，与其抑制相关的IGF-1R构象变化可通过一种称为偏向信号传导的过程，以激酶非依赖性方式优先激活MAPK通路。我们在一组具有不同MAPK和p53突变状态的皮肤黑色素瘤细胞系中，探讨了偏向性IGF-1R信号传导对MAPK抑制反应的影响。针对IGF-1R的特异性siRNA以平衡的方式下调受体及其所有信号传导，而小分子Nutlin-3靶向IGF-1R则使受体降解与短暂的偏向性pERK1/2活性平行，这两种策略均与MEK1/2抑制协同作用。另一方面，靶向抗体（Figitumumab）下调IGF-1R会诱导一种偏向性受体构象，即使受体暴露于平衡的天然配体IGF-1时这种构象也会保留。这一过程维持了MAPK活性，并与MEK1/2抑制相互竞争。我们的结果表明，下调IGF-1R提供了一种提高黑色素瘤细胞对MAPK抑制敏感性的方法，并强调控制偏向信号传导可为多重打击疗法提供更高的特异性和精准性。
