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

Naida Suleymanova,Caitrin Crudden,Anica Dricu,Leonard Girnita,Claire Worrall,Ada Girnita

doi:10.18632/oncotarget.19286

Abstract

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.

Highlights

Malignant melanoma is the deadliest form of skin cancer and has shown increasing incidence since the 1970s
Our results indicate that insulin-like growth factor type 1 receptor (IGF-1R) down-regulation offers an approach to increase the sensitivity of melanoma cells to mitogen activated protein kinase (MAPK) inhibition, and highlights that controlling biased signaling could provide greater specificity and precision required for multi-hit therapy
It should be noted here that this biased signaling is induced in response to the prototypical balanced ligand (IGF-1), indicating that a biased-receptor conformation stabilized by CP-pretreatment is preserved even after CP treatment is removed. Taken together these results demonstrate decreased IGF-1R signaling following all treatment regimens, balanced in the case of small interfering RNA (siRNA), and transient or sustained biased MAPK signaling in the case of Nutlin-3 and CP, respectively

Summary

Introduction

Malignant melanoma is the deadliest form of skin cancer and has shown increasing incidence since the 1970s. The last few decades have seen significant advancement in our understanding of the melanoma pathogenesis, in particular recognition of the hyperactive mitogen activated protein kinase (MAPK) signaling cascade, most frequently through oncogenic mutation in the B-RAF or RAS genes, as a key molecular mechanism driving the disease [2]. This aberrant MAPK pathway mediates a spectrum of cancer promoting bioactivities, including survival, proliferation and metastasis [3, 4]. Among various RTKs found to be associated with resistance to MAPK [13,14,15], studies on post-relapse tumor samples have shown increased expression and/or signaling of the insulin-like growth factor type 1 receptor (IGF-1R) [14, 16, 17]

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