title: Efficacy of and resistance to anti-IGF-1R therapies in Ewing's sarcoma is dependent on insulin receptor signaling.
abstract: Identification of patient selection criteria and understanding of the potential mechanisms involved in the development of resistance are crucial for an appropriate and successful design of clinical trials with anti-insulin-like growth factor (IGF)-1R therapies. Few Ewing's sarcomas are highly sensitive to IGF-1R targeting and understanding the reason why, may hold the secret to improve successful treatments. In this paper, we show that a major mechanism of resistance to highly specific inhibitors of IGF-1R, either antibodies or tyrosine kinase inhibitors may involve enhanced insulin receptor (IR)-A homodimer formation and IGF-2 production. Resistant cells are able to switch from IGF-1/IGF-1R to IGF-2/IR-A dependency to maintain sustained activation of AKT and ERK1/2, proliferation, migration and metastasis. These cells also showed higher proliferative response to insulin, in keeping with a switch towards insulin pathways sustaining proliferation and malignancy, rather than metabolism. Our findings demonstrate a role for IR-A in eliciting intrinsic and adaptive resistance to anti-IGF-1R therapies. Thus, we indicate that tumors with low IGF-1R:IR ratio are unlikely to greatly benefit from anti-IGF-1R therapies and that the efficacy of anti-IGF-1R therapies should be evaluated in relationship to the IR-A:IGF-1R ratio in cancer cells. Moreover, we provide evidences supporting IR-A as an important target in sarcoma therapy.
authors.affiliation: Laboratory of Experimental Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Garofalo
authors.forename: M C
authors.initials: MC
authors.lastname: Manara
authors.forename: G
authors.initials: G
authors.lastname: Nicoletti
authors.forename: M T
authors.initials: MT
authors.lastname: Marino
authors.forename: P-L
authors.initials: PL
authors.lastname: Lollini
authors.forename: A
authors.initials: A
authors.lastname: Astolfi
authors.forename: G
authors.initials: G
authors.lastname: Pandini
authors.forename: J A
authors.initials: JA
authors.lastname: López-Guerrero
authors.forename: K-L
authors.initials: KL
authors.lastname: Schaefer
authors.forename: A
authors.initials: A
authors.lastname: Belfiore
authors.forename: P
authors.initials: P
authors.lastname: Picci
authors.forename: K
authors.initials: K
authors.lastname: Scotlandi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051379:Mice; D017526:Receptor, IGF Type 1 / Q000032:analysis / Q000037:antagonists & inhibitors*; D011972:Receptor, Insulin / Q000032:analysis / Q000502:physiology*; D012512:Sarcoma, Ewing / Q000188:drug therapy*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin