IGF-1R Inhibition Activates a YES/SFK Bypass Resistance Pathway: Rational Basis for Co-Targeting IGF-1R and Yes/SFK Kinase in Rhabdomyosarcoma.

Abstract

The insulin-like growth factor 1 receptor (IGF-1R) has surfaced as a significant target in multiple solid cancers due to its fundamental roles in pro-survival and anti-apoptotic signaling. However, development of resistance to IGF-1R blockade represents a significant hindrance and limits treatment efficacy in the clinic. In this study, we identified acquired resistance to IGF-1R blockade with R1507, an antibody against IGF-1R, and with BMS-754807, a small molecular inhibitor of IGF-1R/insulin receptor (IR). We showed that treatment with an IGF-IR antibody, R1507, or an IR/IGF-IR kinase inhibitor, BMS-754807, was associated with increased activation of YES/SRC family tyrosine kinase (SFK) in rhabdomyosarcoma (RMS). Combining anti-IGF-1R agents with SFK inhibitors resulted in blockade of IGF-1R inhibition-induced activation of YES/SFK and displayed advantageous antitumor activity in vitro and in vivo. Our data provide evidence that IGF-1R blockade results in activation of the YES/SRC family kinase bypass resistance pathway in vitro and in vivo. This may be of particular clinical relevance since both Yes and IGF components are overexpressed in RMS. Increased YES/SFK activation might serve as a clinical biomarker for predicting tumor resistance to IGF-1R inhibition. Dual inhibition of IGF-1R and SFK may have a broader and enhanced clinical benefit for patients with RMS.

• Authors: Xiaolin Wan, Choh Yeung, Christine Heske, Arnulfo Mendoza, Lee J Helman
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 17 Issue 4 Pg. 358-66 (Apr 2015) ISSN: 1476-5586 [Electronic] United States
• PMID: 25925378 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: Published by Elsevier Inc.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• BMS 754807
• Biomarkers, Tumor
• Protein Kinase Inhibitors
• Pyrazoles
• Triazines
• Receptor, IGF Type 1
• Receptor, Insulin
• Proto-Oncogene Proteins c-yes
• YES1 protein, human
• src-Family Kinases
• teprotumumab

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (pharmacology)
• Biomarkers, Tumor (metabolism)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects)
• Female
• Humans
• Mice
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-yes (metabolism)
• Pyrazoles (pharmacology)
• Receptor, IGF Type 1 (antagonists & inhibitors, metabolism)
• Receptor, Insulin (antagonists & inhibitors, metabolism)
• Rhabdomyosarcoma (drug therapy, metabolism)
• Triazines (pharmacology)
• Xenograft Model Antitumor Assays
• src-Family Kinases (metabolism)