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Identification of both common and distinctive mechanisms of resistance to different anti-IGF-1R agents in Ewing’s sarcoma

Garofalo, Cecilia, Mancarella, Caterina, Grilli, Andrea, Manara, Maria Cristina, Astolfi, Annalisa, Marino, Maria Teresa, Conte, Alexia, Sigismund, Sara, Carè, Alessandra, Belfiore, Antonino, Picci, Piero and Scotlandi, Katia (2012) Identification of both common and distinctive mechanisms of resistance to different anti-IGF-1R agents in Ewing’s sarcoma. Molecular Endocrinology, 26 (9). pp. 1603-1616. ISSN 0888-8809


IGF system contributes significantly to many human tumors malignancy. Currently most of the therapeutic agents, antibodies (HAb) or tyrosine kinase inhibitors (TKI), have been designed to specifically target IGF-1R. In Ewing’s sarcoma, despite the presence of the target and strong preclinical evidences supporting the potential value of anti-IGF-1R agents, less than 10% of cases responded to this therapy. We have recently provided evidences for a compensatory role of IR-A when IGF-1R is disrupted and indicated the relationship between the two receptors as one mechanism responsible of acquired and intrinsic resistance to selective anti-IGF-1R therapy.
In this study we compared resistance mechanisms for two specific anti-IGF-IR human antibodies, AVE1642 or CP751,871(Fugitumumab), and an anti-IGF-IR TKI NVP-AEW541. Ewing’s sarcoma cell variants resistant to the three drugs have been genetically and molecularly analyzed to identify common mechanisms of acquired resistance as well as distinct mechanisms, so to provide insights to be used for reversal or prevention of resistance. We confirm the transcriptional up-regulation of IR-A and IGF-2 as a common mechanism of resistance to anti-IGF-IR agents in Ewing’s sarcoma. In addition, we observed common upregulation of all the major mediators of MAPK/ERK pathway in the three resistant variants, in keeping with the maintenance of growth abilities and stemness features of parental cells. Furthermore, annotation analysis of the gene expression profiles pointed out that meanwhile the resistance to HAbs involves genes regulating neural differentiation and angiogenesis, the resistance to AEW541 induces alterations in inflammation and stress-responses, as well as in antigen presentation. Consistently, we observed inhibition of two specific markers of neural differentiation in cell variants resistant to HAbs compared to TKI resistant cell line or parental cells.
In conclusion, while the IGF system clearly remains an important therapeutic target, it is becoming clear that the complexity of this pathway requires analytical evaluation of its components to better select the patients and guide individualized treatment combination.

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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15