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

// Naida Suleymanova 1, * , Caitrin Crudden 1, * , Claire Worrall 1 , Anica Dricu 2 , Ada Girnita 1, 3 and Leonard Girnita 1 1 Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden 2 Biochemistry Unit, University of Medicine and Pharmacy of Craiova, Craiova, Romania 3 Dermatology Department, Karolinska University Hospital, Stockholm, Sweden * These authors have contributed equally to this work Correspondence to: Leonard Girnita, email: Leonard.Girnita@ki.se 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.