Redundant Signaling as the Predominant Mechanism for Resistance to Antibodies Targeting the Type-I Insulin-Like Growth Factor Receptor in Cells Derived from Childhood Sarcoma

• Published in: Molecular cancer therapeutics Vol. 22; no. 4; pp. 539 - 550
• Main Authors: Shackleford, Terry J, Hariharan, Seethalakshmi, Vaseva, Angelina V, Alagoa, Karina, Espinoza, Maricruz, Bid, Hemant K, Li, Fuyang, Zhong, Haihong, Phelps, Doris A, Roberts, Ryan D, Cam, Hakan, London, Cheryl A, Guttridge, Denis C, Chen, Yidong, Rao, Manjeet, Shiio, Yuzuru, Houghton, Peter J
• Format: Journal Article
• Language: English
• Published: United States 03-04-2023
• Subjects: Antibodies, Monoclonal - pharmacology; Cell Cycle Proteins; Cell Line, Tumor; Child; Humans; Nuclear Proteins; Receptor, IGF Type 1; Receptors, Somatomedin; Sarcoma - drug therapy; SOXF Transcription Factors; Transcription Factors
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-20-0625

Antibodies targeting insulin-like growth factor 1 receptor (IGF-1R) induce objective responses in only 5% to 15% of children with sarcoma. Understanding the mechanisms of resistance may identify combination therapies that optimize efficacy of IGF-1R-targeted antibodies. Sensitivity to the IGF-1R-targeting antibody TZ-1 was determined in rhabdomyosarcoma and Ewing sarcoma cell lines. Acquired resistance to TZ-1 was developed and characterized in sensitive Rh41 cells. The BRD4 inhibitor, JQ1, was evaluated as an agent to prevent acquired TZ-1 resistance in Rh41 cells. The phosphorylation status of receptor tyrosine kinases (RTK) 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 phosphorylated RTKs 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 with other IGF-1R-targeted antibodies tested against this model.