Dual targeting of IGF-1R and ErbB3 as a potential therapeutic regimen for ovarian cancer.

Abstract

Therapeutically targeting receptor tyrosine kinases has proven to be paramount to overcoming chemotherapy resistance in several cancer indications, improving patient outcomes. Insulin-Like Growth Factor Receptor 1 (IGF-1R) and Epidermal Growth Factor Receptor 3 (ErbB3) have been implicated as two such drivers of resistance, however their simultaneous role in ovarian cancer chemotherapy resistance remains poorly elucidated. The aim of this work is to determine the effects of dual IGF-1R/ErbB3 inhibition on ovarian cancer cell signaling, growth, and in vivo efficacy. Assessment of in vitro chemotherapy response across a panel of ovarian cancer cell lines revealed that increased IGF-1R cell surface expression correlates with decreased sensitivity to chemotherapy, and that growth induced by IGF-1R and ErbB3 ligands is blocked by the tetravalent bispecific antibody targeting IGF-1R and ErbB3, istiratumab. In vitro chemotherapy treatment increased ovarian cancer cell line capacity to activate prosurvival PI3K signaling in response to ligand, which could be prevented with istiratumab treatment. Furthermore, in vivo efficacy of standard of care chemotherapies using a xenograft model of ovarian cancer was potentiated with istiratumab. Our results suggest a role for IGF-1R and ErbB3 in driving chemotherapy resistance of ovarian cancer.

• Authors: Adam J Camblin, Gege Tan, Michael D Curley, Isabel Yannatos, Sergio Iadevaia, Victoria Rimkunas, Mari Mino-Kenudson, Troy Bloom, Birgit Schoeberl, Daryl C Drummond, Alexey A Lugovskoy, Chrystal U Louis, Vasileios Askoxylakis
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 16832 (11 14 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31728045 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• IGF1R protein, human
• liposomal doxorubicin
• Polyethylene Glycols
• Doxorubicin
• ERBB3 protein, human
• Receptor, ErbB-3
• Receptor, IGF Type 1
• Paclitaxel
• Cisplatin
• Istiratumab

Topics

• Animals
• Antibodies, Monoclonal, Humanized (administration & dosage, pharmacology)
• Antineoplastic Agents (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cisplatin (administration & dosage, pharmacology)
• Doxorubicin (administration & dosage, analogs & derivatives, pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mice
• Ovarian Neoplasms (drug therapy, metabolism)
• Paclitaxel (administration & dosage, pharmacology)
• Polyethylene Glycols (administration & dosage, pharmacology)
• Receptor, ErbB-3 (antagonists & inhibitors, metabolism)
• Receptor, IGF Type 1 (antagonists & inhibitors, metabolism)
• Xenograft Model Antitumor Assays