Identification of common and distinctive mechanisms of resistance to different anti-IGF-IR agents in Ewing's sarcoma.
IGF system contributes significantly to many human malignancies. Targeting IGF-I receptor (IGF-IR) has been reported to be active against several tumors, but particular efficacy was observed only against a minority of Ewing's sarcoma patients. Identification of mechanisms of acquired resistance to anti-IGF-IR agents is mandatory to individualize their use in clinics and optimize cure costs. In this study, we compared gene expression profiles of cells made resistant with three different anti-IGF-IR drugs (human antibodies AVE1642, Figitumumab, or tyrosine kinase inhibitor NVP-AEW541) to highlight common and distinctive mechanisms of resistance. Among common mechanisms, we identified two molecular signatures that distinguish sensitive from resistant cells. Annotation analysis indicated some common altered pathways, such as insulin signaling, MAPK pathway, endocytosis, and modulation of some members of the interferon-induced transmembrane protein family. Among distinctive pathways/processes, resistance to human antibodies involves mainly genes regulating neural differentiation and angiogenesis, whereas resistance to NVP-AEW541 is mainly associated with alterations in genes concerning inflammation and antigen presentation. Evaluation of the common altered pathways indicated that resistant cells seem to maintain intact the IGF-IR internalization/degradation route of sensitive cells but constantly down-regulated its expression. In resistant cells, the loss of proliferative stimulus, normally sustained by IGF-I/IGF-IR autocrine loop in Ewing's sarcoma cells, is compensated by transcriptional up-regulation of IGF-II and insulin receptor-A; this signaling seems to favor the MAPK pathway over the v-akt murine thymoma viral oncogene homolog 1 pathway. Overall, complexity of IGF system requires analytical evaluation of its components to select those patients that may really benefit from this targeted therapy and support the idea of cotargeting IGF-IR and insulin receptor-A to increase the efficacy.
Centro Riferimento Specialistico Development of Biomolecular Therapies, Experimental Oncology Laboratory, Rizzoli Orthopedic Institute, 40136 Bologna, Italy.
Cecilia
C
Garofalo
Caterina
C
Mancarella
Andrea
A
Grilli
Maria Cristina
MC
Manara
Annalisa
A
Astolfi
Maria Teresa
MT
Marino
Alexia
A
Conte
Sara
S
Sigismund
Alessandra
A
Carè
Antonino
A
Belfiore
Piero
P
Picci
Katia
K
Scotlandi
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016756:Immunoglobulins, Intravenous; C501177:NVP-AEW541; D011743:Pyrimidines; D011758:Pyrroles; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; C525021:figitumumab; C545477:AVE1642