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