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

Helen J. Huang, Laura S. Angelo, Jordi Rodon, Michael Sun, Klaus Peter Kuenkele, Henrique A. Parsons, Jonathan C. Trent, Razelle Kurzrock

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26 Scopus citations

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.

Original languageEnglish (US)
Article numbere26060
JournalPloS one
Volume6
Issue number10
DOIs
StatePublished - Oct 11 2011

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Huang, H. J., Angelo, L. S., Rodon, J., Sun, M., Kuenkele, K. P., Parsons, H. A., Trent, J. C., & Kurzrock, R. (2011). 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. PloS one, 6(10), [e26060]. https://doi.org/10.1371/journal.pone.0026060