Abstract LB-235: IGF-1R/mTOR blockade and mechanisms of resistance in Ewing sarcoma

Abstract

Abstract Ewing sarcoma (ES), the second most common bone cancer in adolescents and young adults, is dependent upon the insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) cell-signaling axis for malignancy, survival, and metastasis. Therapies co-targeting IGF-1R and mTOR have demonstrated remarkable, although ephemeral, clinical responses in a subset of ES patients. However, the mechanisms of resistance and applicable strategies for overcoming drug resistance to IGF-1R/mTOR blockade are still undefined. To elucidate predominant mechanism(s) of acquired drug resistance, while identifying synergistic drug combinations that improve clinical efficacy, we generated ES cell lines resistant to IGF-1R or mTOR targeted therapy. Two small-molecule inhibitors of IGF-1R were chosen, NVP-ADW-742 (IGF-1R-selective) and OSI-906 (a dual IGF-1R/insulin receptor alpha [IR-α] inhibitor). Chronic ridaforolimus exposure led to mTOR-resistant ES cell lines. Reverse phase protein lysate arrays (RPPA) revealed proteomic changes linked to IGF-1R/mTOR resistance and selected proteins were validated using in vitro cell-based assays, xenografts, and human clinical samples. Novel mechanisms of resistance (MOR) occurred in NVP-ADW-742-, OSI-906-, and ridaforolimus-resistant cells. Of particular clinical relevance given OSI-906's ongoing phase 1b/2 clinical trials, the MOR varied depending upon whether IGF-1R or both IGF-1R and IR-α were targeted. Key proteomic alterations present in vitro also occurred in ES xenografts and human tumor specimens exposed to these agents. Novel synergistic drug combinations (e.g., inhibitors of Mnk and mTOR) were identified in vitro that are currently undergoing prospective validation. In conclusion, we discovered new druggable targets expressed by chemo-resistant ES cells, xenografts, and relapsed human tumors. Joint suppression of these newfound targets with IGF-1R or mTOR enhanced the antineoplastic effect of IGF-1R/mTOR blockade and suggests the need for in vivo validation. Citation Format: Salah-Eddine LAMHAMEDI CHERRADI, Brian Menegaz, Vandhana Ramamoorthy, Joseph Ludwig. IGF-1R/mTOR blockade and mechanisms of resistance in Ewing sarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-235.