Constraints on the p53 tumor suppressor pathway have long been associated with the progression, therapeutic resistance, and poor prognosis of melanoma, the most aggressive form of skin cancer. Likewise, the insulin-like growth factor type 1 receptor (IGF1R) is recognized as an essential coordinator of transformation, proliferation, survival, and migration of melanoma cells. Given that β-arrestin (β-arr) system critically governs the anti/pro-tumorigenic p53/IGF1R signaling pathways through their common E3 ubiquitin-protein ligase MDM2, we explore whether unbalancing this system downstream of IGF1R can enhance the response of melanoma cells to chemotherapy. Altering β-arr expression demonstrated that both β-arr1-silencing and β-arr2-overexpression (-β-arr1/+β-arr2) facilitated nuclear-to-cytosolic MDM2 translocation accompanied by decreased IGF1R expression, while increasing p53 levels, resulting in reduced cell proliferation/survival. Imbalance towards β-arr2 (-β-arr1/+β-arr2) synergizes with the chemotherapeutic agent, dacarbazine, in promoting melanoma cell toxicity. In both 3D spheroid models and in vivo in zebrafish models, this combination strategy, through dual IGF1R downregulation/p53 activation, limits melanoma cell growth, survival and metastatic spread. In clinical settings, analysis of the TCGA-SKCM patient cohort confirms β-arr1/β-arr2+ imbalance as a metastatic melanoma vulnerability that may enhance therapeutic benefit. Our findings suggest that under steady-state conditions, IGF1R/p53-tumor promotion/suppression status-quo is preserved by β-arr1/2 homeostasis. Biasing this balance towards β-arr2 can limit the protumorigenic IGF1R activities while enhancing p53 activity, thus reducing multiple cancer-sustaining mechanisms. Combined with other therapeutics, this strategy improves patient responses and outcomes to therapies relying on p53 or IGF1R pathways.

Implications:

Altogether, β-arrestin system bias downstream IGF1R is an important metastatic melanoma vulnerability that may be conductive for therapeutic benefit.

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