Oncotarget

Research Papers:

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

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

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Oncotarget. 2017; 8:82256-82267. https://doi.org/10.18632/oncotarget.19286

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Abstract

Naida Suleymanova1,*, Caitrin Crudden1,*, Claire Worrall1, Anica Dricu2, Ada Girnita1,3 and Leonard Girnita1

1Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

2Biochemistry Unit, University of Medicine and Pharmacy of Craiova, Craiova, Romania

3Dermatology Department, Karolinska University Hospital, Stockholm, Sweden

*These authors have contributed equally to this work

Correspondence to:

Leonard Girnita, email: [email protected]

Keywords: biased signaling, rtks, functional selectivity, cancer, targeted therapy

Received: March 31, 2017     Accepted: June 17, 2017     Published: July 17, 2017

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.


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