Targeting the Insulin-Like Growth Factor Pathway in Rhabdomyosarcomas: Rationale and Future Perspectives

Figure 1

A simple schema of the IGF pathway and approaches to its inhibition. Insulin, IGF2 and IGF1 bind to their specific receptors including IGF1R, IGF2R, IR and hybrid receptors. Ligand binding results in the autophosphorylation of the tyrosine residues on each receptor, leading to recruitment of the adaptor proteins IRS and Shc to the receptor β-subunits intracellular domains. This process activates different signaling cascades through the PI3K-AKT and the RAS/RAF/MEK/ERK pathways resulting in stimulation of translation and cell cycle progression, increased proliferation and growth and inhibition of apoptosis. The dashed arrows indicate potential feedback mechanisms and points for strategic intervention to inhibit IGF1R signaling using anti-IGF1R mAbs or tyrosine kinase inhibitors (TKIs). Relevant downstream intracellular tyrosine kinase proteins to inhibit include PI3K, AKT, RAF, MEK and mTOR.