Abstract Antibodies targeting IGF-1R induce objective responses in only 5-15% of children with sarcoma. Understanding mechanisms of resistance may identify combination therapies that optimize efficacy of IGF-1R-targeted antibodies. Sensitivity to the IGF1R-targeting antibody TZ-1 was determined in rhabdomyosarcoma (RMS) and Ewing sarcoma (EWS) cell lines. Acquired resistance to TZ-1 was developed and characterized in sensitive Rh41 cells. BRD4 inhibitor, JQ1 was evaluated as an agent to prevent acquired TZ-1 resistance in Rh41 cells. The phosphorylation status of RTKs was assessed. Sensitivity to TZ-1 in vivo was determined in Rh41 parental and TZ-1-resistant xenografts. Of 20 sarcoma cell lines, only Rh41 was sensitive to TZ-1. Cells intrinsically resistant to TZ-1 expressed multiple (>10) activated RTKs or a relatively less complex set of activated RTKs (~5). TZ-1 decreased the phosphorylation of IGF-1R, but had little effect on other pRTKs in all resistant lines. TZ-1 rapidly induced activation of RTKs in Rh41 that was partially abrogated by knockdown of SOX18 and JQ1. Rh41/TZ-1 cells selected for acquired resistance to TZ-1 constitutively expressed multiple activated RTKs. TZ-1 treatment caused complete regressions in Rh41 xenografts, and was significantly less effective against the Rh41/TZ-1 xenograft. Intrinsic resistance is a consequence of redundant signaling in pediatric sarcoma cell lines. Acquired resistance in Rh41 cells, is associated with rapid induction of multiple RTKs indicating a dynamic response to IGF-1R blockade and rapid development of resistance. The TZ-1 antibody had greater antitumor activity against Rh41 xenografts compared to other IGF-1R-targeted antibodies tested against this model.