Targeting the IGF1R signaling for anti-cancer therapy

Activation of Insulin-like growth factor -1 receptor (IGF1R) signaling is pivotal for development of many types of cancer and, therefore, strategies of targeting this pathway for cancer treatment represents a valid approach. However, such strategies have been largely undermined by the widespread resistance observed in tumor cells. One of the contributors to this resistance is the activation of non-canonical β-arr1/2 system downstream of IGF1R, which leads to differential effects depending on this system’s balance. It can facilitate protumorigenic, proliferative and survival signaling within tumor cells, and, on the other hand, could initiate/activate tumor-suppressor pathways.

This thesis provides an extensive review of the IGF1R contributions to the maintenance of the malignant phenotype. The focus is on the insights into both the canonical pathways downstream of IGF1R as well as their relationship with the more recently identified non-canonical β-arr1/2 controlled pathways. Although a direct manipulation of β-arr1/2 system to develop therapeutic strategies remains challenging, this thesis discusses the potential of using such approach downstream IGF1R to improve management of cancer patients. Within the frame of targeting non-canonical β-arr1/2 controlled pathways, as a proof of- concept, the thesis specifically discussed three studies. Study I addresses the concept of shifting the balance towards the β-arr2 predominance. This was achieved in melanoma cells by either overexpressing β-arr2 and/or silencing β- arr1. In combination with a common treatment modality in melanoma (DTIC), this approach led to a significant inhibition of melanoma cell proliferation. This study suggests that a β-arr2-predominant status, in addition to downregulating IGF1R, provides context for p53 activation thereby suppressing tumor growth. Furthermore, this study provides rationale for combining p53-activating therapeutics with β-arr2-dominant conditions.

The second study reviewed in this thesis describes the use of Paroxetine (PX), a GRK2 inhibitor, to create a β-arr1-predominant cellular environment. Under these conditions, the IGF1R is downregulated, which has by itself an antitumorigenic effect. However, shift towards β-arr1-predominant conditions can also activate some pro-tumorigenic effects, which were mitigated using inhibitors of the MAPK/PI3K downstream signaling pathway resulting in inhibition of tumor cell proliferation. This study provides rationale for combining targeted signaling therapeutics with β-arr1-dominant conditions. The third study reviewed in this thesis describes the cellular responses to different antibodies targeting IGF1R. The study analyzes the IGF1R degradation, internalization and also downstream signaling in connection to β-arr1/2 system activity. The study suggests the potential of different anti-IGF1R antibodies to produce a desired shift towards β-arr1 or β-arr2-dominant condition. In conclusion, this thesis provides new insights into the IGF1R signaling and β- arr1/2 involvement and highlights potential therapeutic strategies for overcoming resistance in cancer treatments targeting IGF1R.