Resistance pathways relevant to insulin-like growth factor-1 receptor-targeted therapy.
The dysregulation of insulin-like growth factor (IGF) signaling has been implicated as a critical contributor to malignant transformation, proliferation, survival, migration and resistance to anticancer therapies. As a result, IGF signaling has become an attractive target for the development of novel anticancer agents, and a large number of compounds, including blocking antibodies and tyrosine kinase inhibitors targeting the key signaling kinase of the IGF system, the IGF-1 receptor (IGF-1R), are in preclinical and clinical development. Although most tumors express the IGF-1R, expression alone is unlikely to be sufficient for sensitivity to IGF-targeted treatment. An understanding of the IGF signaling system and its downstream effectors is important, as this information will allow appropriate molecular markers of sensitivity to be determined, thus providing the rationale for combining IGF-1R blockade with other therapies to overcome resistance. This review highlights some of the preclinical and early clinical data on determinants of sensitivity to IGF targeting in human cancers, and reviews the rationale for targeting other tyrosine kinases, such as the insulin receptor and members of the EGFR family, to overcome intrinsic resistance to targeted IGF-1R therapy.
Hendrickson
Andrea Wahner
AW
Mayo Clinic College of Medicine, Division of Medical Oncology, Rochester, MN 55905, USA.
Haluska
Paul
P
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D016503:Drug Delivery Systems; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000503:physiopathology; D017526:Receptor, IGF Type 1 / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D017526:Receptor, IGF Type 1