Enhanced response of melanoma cells to MEK inhibitors following unbiased IGF-1R down-regulation

13Citations
Citations of this article
16Readers
Mendeley users who have this article in their library.

Abstract

Due to its ability to compensate for signals lost following therapeutic MAPKinhibition, 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 kinaseindependent 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.

Cite

CITATION STYLE

APA

Suleymanova, N., Crudden, C., Worrall, C., Dricu, A., Girnita, A., & Girnita, L. (2017). Enhanced response of melanoma cells to MEK inhibitors following unbiased IGF-1R down-regulation. Oncotarget, 8(47), 82256–82267. https://doi.org/10.18632/oncotarget.19286

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free