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

Adam J Camblin,Mari Mino-Kenudson,Gege Tan,Chrystal U Louis,Vasileios Askoxylakis,Alexey A Lugovskoy,Michael D Curley,Victoria Rimkunas,Sergio Iadevaia,Birgit Schoeberl,Troy Bloom,Isabel Yannatos,Daryl C Drummond

doi:10.1038/s41598-019-53322-y

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.

Highlights

Targeting receptor tyrosine kinases has proven to be paramount to overcoming chemotherapy resistance in several cancer indications, improving patient outcomes
Area under the curve (AUC) of the chemotherapy dose response from Fig. 1A was plotted against receptor expression from Fig. 1B, and the correlation between chemotherapy resistance and receptor tyrosine kinases (RTKs) expression was determined
We show that insulin growth factor 1 receptor (IGF-1R), ErbB3 and their ligands are expressed in a significant proportion of ovarian cancer patient samples

Summary

Introduction

Targeting receptor tyrosine kinases has proven to be paramount to overcoming chemotherapy resistance in several cancer indications, improving patient outcomes. 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. Initial treatment responses are common, they are usually followed by disease recurrence This underscores the urgent need for a deeper understanding of ovarian cancer pathophysiology and the development of novel therapeutic approaches. In this study we characterized the impact of IGF-1R and ErbB3 in ovarian cancer growth and therapy resistance and reveal strategies to re-sensitize ovarian cancer cells to clinically relevant chemotherapy using istiratumab, a fully human bispecific tetravalent IGF-1R- and ErbB3-targeting antibody, composed of a monoclonal IgG1 antibody, engineered to contain two single-chain Fv fragments[12,13]. Our data indicate a potential benefit of dual IGF-1R/ErbB3 inhibition for ovarian cancer treatment, and highlight the potential impact of istiratumab in combination with standard of care chemotherapy to treat ovarian cancer

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Conclusion