R1507, an Anti-Insulin-Like Growth Factor-1 Receptor (IGF-1R) Antibody, and EWS/FLI-1 siRNA in Ewing's Sarcoma: Convergence at the IGF/IGFR/Akt Axis

Abstract

A subset of patients with Ewing's sarcoma responds to anti-insulin-like growth factor-1 receptor (IGF-1R) antibodies. Mechanisms of sensitivity and resistance are unknown. We investigated whether an anti-IGF-1R antibody acts via a pathway that could also be suppressed by small interfering (si) RNA against the EWS/FLI-1 fusion protein, the hallmark of Ewing's sarcoma. The growth of two Ewing's sarcoma cell lines (TC-32 and TC-71) was inhibited by the fully human anti-IGF-1R antibody, R1507 (clonogenic and MTT assays). TC-32 and TC-71 cells express high levels of IGF-2, while RD-ES and A4573 Ewing's cell lines, which were less responsive to R1507 in our assays, express low or undetectable IGF-2, respectively. TC-71 cells also expressed high levels of IGF-1R, and R1507 decreased steady-state levels of this receptor by internalization/degradation, an effect which was associated with a decrease in p-IGF-1R, p-IRS-1, and p-Akt. EWS/FLI-1 siRNA also decreased p-Akt, due to its ability to increase IGF-BP3 levels and subsequently decrease IGF-1 and IGF-2 levels, thus inhibiting signaling through p-IGF-1R. This inhibition correlated with growth suppression and apoptosis. The attenuation of Akt activation was confirmed in TC-71 and HEK-293 (human embryonic kidney) cells by transfecting them with IGF-1R siRNA. We conclude that antibodies and siRNA to IGF-1R, as well as siRNA to EWS/FLI-1, act via intersecting IGF/IGF-1R signals that suppress a common point in this pathway, namely the phosphorylation of Akt.

Retracted: Let-7a Functions as a Tumor Suppressor in Ewing's Sarcoma Cell Lines Partly by Targeting Cyclin-Dependent Kinase 6

“…Under certain conditions, miRNAs can switch from their repression to activation function through upregulating their targets (Vasudevan et al, 2007), such as let-7a. Lu et al (2007Lu et al ( , 2011 found that ectopic let-7a expression significantly activated the expression of insulin-like growth factor (IGF)-II, which was reported to play an important role in the tumor progression of ES (Zhan et al, 1995), and some clinical trials that target IGF/IGF-1R/Akt axis are under investigation for future ES treatments (Huang et al, 2011). Thus, these conflicting reports promote us to explore the exact function and relative molecular mechanisms of let-7a in ES.…”

Antitumor efficacy of the heparan sulfate mimic roneparstat (SST0001) against sarcoma models involves multi-target inhibition of receptor tyrosine kinases

“…Figure 2C shows that, in the ES cell line TC71, drug treatment was able to markedly reduce IGF1R phosphorylation at Y1135/Y1136, two major autophosphorylation sites in the receptor activation loop [20]. TC71 cells carry the prototypical EWS-FLI1 fusion and, consistently with a common pattern of IGF/IGF1R axis deregulation, express high levels of IGF1R and of both IGF1 and IGF2 likely involved in autocrine loops [21]. Nonetheless, IGF1R remains highly responsive to exogenous IGF2 in TC71 cells.…”

Can we unlock the potential of IGF-1R inhibition in cancer therapy?

“…In addition, IGF-1R antibodies were recently reported to have single agent activity in recurrent ovarian cancer and relapsed thymoma, although thymoma treatment was associated with the development of autoimmune conditions including red cell aplasia [45,46]. Activity in EWS and childhood sarcomas may be a consequence of functional interactions between oncogenic fusion proteins (EWS-FLI1 and related fusion partners) and the IGF pathway [47–50]. …”