β-Arrestin–biased agonism as the central mechanism of action for insulin-like growth factor 1 receptor–targeting antibodies in Ewing’s sarcoma

Abstract

Owing to its essential role in cancer, insulin-like growth factor type 1 receptor (IGF-1R)-targeted therapy is an exciting approach for cancer treatment. However, when translated into clinical trials, IGF-1R-specific antibodies did not fulfill expectations. Despite promising clinical responses in Ewing's sarcoma (ES) phase I/II trials, phase III trials were discouraging, requiring bedside-to-bench translation and functional reevaluation of the drugs. The anti-IGF-1R antibody figitumumab (CP-751,871; CP) was designed as an antagonist to prevent ligand-receptor interaction but, as with all anti-IGF-1R antibodies, it induces agonist-like receptor down-regulation. We explored this paradox in a panel of ES cell lines and found their sensitivity to CP was unaffected by presence of IGF-1, countering a ligand blocking mechanism. CP induced IGF-1R/β-arrestin1 association with dual functional outcome: receptor ubiquitination and degradation and decrease in cell viability and β-arrestin1-dependent ERK signaling activation. Controlled β-arrestin1 suppression initially enhanced CP resistance. This effect was mitigated on further β-arrestin1 decrease, due to loss of CP-induced ERK activation. Confirming this, the ERK1/2 inhibitor U0126 increased sensitivity to CP. Combined, these results reveal the mechanism of CP-induced receptor down-regulation and characteristics that functionally qualify a prototypical antagonist as an IGF-1R-biased agonist: β-arrestin1 recruitment to IGF-1R as the underlying mechanism for ERK signaling activation and receptor down-regulation. We further confirmed the consequences of β-arrestin1 regulation on cell sensitivity to CP and demonstrated a therapeutic strategy to enhance response. Defining and suppressing such biased signaling represents a practical therapeutic strategy to enhance response to anti-IGF-1R therapies.

The dichotomy of the Insulin-like growth factor 1 receptor: RTK and GPCR: friend or foe for cancer treatment?

“…As an example, anti-IGF-1R antibodies were designed to achieve maximum binding to the receptor, with the intention of competing with natural agonists [157]. In the drug screening stages the assays were limited to confirmation of their inhibitory effects on IGF-1 induced receptor tyrosine phosphorylation and PI3K/Akt signalling [16,27,118,119,148].…”

“…Anti-IGF-1R therapy efficacy was proven to be highly dependent on the expression of β-arrestin 1 and co-targeting β-arrestin 1 mediated signalling allowed a greater degree of therapeutic modulation [157]. Notably, a similar mechanism of β-arrestin importance was demonstrated in the case of PPP; again, mechanistically the agent worked through β-arrestin mediated receptor ubiquitination and downregulation, alongside activation of the β-arrestin 1/ERK second signalling wave [144].…”

“…However, in clinical settings, treatment with anti-IGF-1R antibodies only induced clinical responses in some cases of Ewing's sarcoma (ES) [61,99,100] and selected cases of lung carcinoma [22,48,106]. Notably, all anti-IGF-1R antibodies used in clinical trials, besides inhibiting IGF-1 induced receptor phosphorylation, also trigger receptor downregulation [157].…”

“…This contradiction was recently investigated for the case of anti-IGF-1R antibody (Figitumumab) induced receptor degradation [157].…”

Non-coding RNAs: the cancer genome dark matter that matters!

“…Over the last decade this bi-directional regulatory networks between microRNAs and signaling complexes coordinated by growth factors receptors have received particular attention revealing some conserved modules [60]. Among RTKs, the IGF and EGF system of ligands, receptors and binding proteins are major player in normal cellular growth and differentiation, as well as in cancer development [60][61][62][63]. Both IGF and EGF systems are organized on three distinct levels: (i) the input layer of ligands, receptors and regulatory proteins of ligand-receptor interaction; (ii) the signal transduction layer, coordinated by adaptors and enzymes of the signaling cascades and the (iii) output layer of transcription factors, controlling the biological response.…”