Protein kinase B modulates the sensitivity of human neuroblastoma cells to insulin‐like growth factor receptor inhibition

The potential of the novel insulin‐like growth factor receptor (IGF‐IR) inhibitor NVP‐AEW541 as an antiproliferative agent in human neuroblastoma was investigated. Proliferation of a panel of neuroblastoma cell lines was inhibited by NVP‐AEW541 with IC₅₀ values ranging from 0.15 to 5 μM. Experiments using an IGF‐IR neutralizing antibody confirmed that the IGF‐IR was essential to support growth of neuroblastoma cell lines. The expression levels of the IGF‐IR in individual neuroblastoma cell lines did not correlate with the sensitivities to NVP‐AEW541, while coexpression of the IGF‐IR and the insulin receptor (IR) correlated with lower sensitivity to the inhibitor in some cell lines. Intriguingly, high levels of activation of Akt/protein kinase B (PKB) and phosphorylation of the ribosomal S6 protein were observed in neuroblastoma cell lines with decreased sensitivities to NVP‐AEW541. Inhibition of Akt/PKB activity restored the sensitivity of neuroblastoma cells to the IGF‐IR inhibitor. Transfection of neuroblastoma cells with activated Akt or ribosomal protein S6 kinase (S6K) decreased the sensitivity of the cells to NVP‐AEW541. IGF‐I‐stimulated proliferation of neuroblastoma cell lines was completely blocked by NVP‐AEW541, or by a combination of an inhibitor of phosphoinositide 3‐kinase and rapamycin. In addition to its antiproliferative effects, NVP‐AEW541 sensitized neuroblastoma cells to cisplatin‐induced apoptosis. Together, our data demonstrate that NVP‐AEW541 in combination with Akt/PKB inhibitors or chemotherapeutic agents may represent a novel approach to target human neuroblastoma cell proliferation. © 2006 Wiley‐Liss, Inc.