Targeting Akt to increase the sensitivity of neuroblastoma to chemotherapy: lessons learned from the brain-derived neurotrophic factor/TrkB signal transduction pathway.

Neuroblastoma (NB) is a neural crest precursor cell-derived extracranial solid tumor in children. Patients with a poor prognosis are often resistant to chemotherapy and have tumors that express the neuronal growth/survival factor brain-derived neurotrophic factor and its tyrosine kinase receptor, TrkB. In this article, the authors discuss a growth/survival factor-stimulated mechanism leading to chemoresistance in NB that is mediated by the PI3K/Akt signaling pathway. Besides brain-derived neurotrophic factor/TrkB, other growth/survival factors and their receptors also activate the PI3K/Akt pathway and have the potential to mediate chemoresistance in NB. These findings raise the possibility of a new therapeutic approach in NB that would target Akt, the common downstream mediator of multiple growth/survival factor signaling pathways, to enhance the efficacy of chemotherapeutics. Several classes of Akt inhibitors, including phosphatidylinositol ether lipid analogs, alkylphospholipid analogs, allosteric Akt kinase inhibitors, HSP90 inhibitor and HIV protease inhibitors are discussed.