title: Novel mechanisms of regulation of IGF-1R action: functional and therapeutic implications.
abstract: The IGF-1R pathway is essential for the initiation and progression of many cancers. In contrast to other receptor tyrosine kinases involved in cancer, it is not frequently mutated or amplified. The classical model of signaling through the IGF-1R centers on ligand initiated kinase activation, allowing binding of adaptor molecules and downstream activation of the MAPK and PI3K pathways. The signaling is terminated through receptor ubiquitination and subsequent degradation. To date, therapies targeting IGF-1R have been designed solely aiming to block phosphorylation mediated signaling by preventing receptor-ligand interaction or by limiting kinase activation. Yet, the classical model is insufficient to explain receptor behavior induced by some IGF-1R inhibitors. This review advocates an updated model of IGF-1R signaling, accommodating the "classical" kinase signaling and the IGF-1R-kinase independent signaling thus providing the theoretical background for receptor downregulation induced by IGF-1R inhibitors. This model should be considered for future design of effective therapies targeting the IGF-1R pathway.
authors: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors: Claire
authors: C
authors: Worrall
authors: Daniela
authors: D
authors: Nedelcu
authors: Julianna
authors: J
authors: Serly
authors: Naida
authors: N
authors: Suleymanova
authors: Iulian
authors: I
authors: Oprea
authors: Ada
authors: A
authors: Girnita
authors: Leonard
authors: L
authors: Girnita
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002648:Child; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D017526:Receptor, IGF Type 1