Dual Inhibition of IGF-1R and ErbB3 Enhances the Activity of Gemcitabine and Nab-Paclitaxel in Preclinical Models of Pancreatic Cancer

Purpose: Insulin-like growth factor receptor 1 (IGF-1R) is critically involved in pancreatic Cancer pathophysiology, promoting Cancer cell survival and therapeutic resistance. Assessment of IGF-1R inhibitors in combination with standard-of-care chemotherapy, however, failed to demonstrate significant clinical benefit. The aim of this work is to unravel mechanisms of resistance to IGF-1R inhibition in pancreatic Cancer and develop novel strategies to improve the activity of standard-of-care therapies.Experimental Design: Growth factor screening in pancreatic Cancer cell lines was performed to identify activators of prosurvival PI3K/Akt signaling. The prevalence of activating growth factors and their receptors was assessed in pancreatic Cancer patient samples. Effects of a bispecific IGF-1R and ErbB3 targeting antibody on receptor expression, signaling, Cancer cell viability and Apoptosis, spheroid growth, and in vivo chemotherapy activity in pancreatic Cancer xenograft models were determined.Results: Growth factor screening in pancreatic Cancer cells revealed insulin-like growth factor 1 (IGF-1) and heregulin (HRG) as the most potent Akt activators. Both growth factors reduced pancreatic Cancer cell sensitivity to gemcitabine or paclitaxel in spheroid growth assays. Istiratumab (MM-141), a novel bispecific antibody that blocks IGF-1R and ErbB3, restored the activity of paclitaxel and gemcitabine in the presence of IGF-1 and HRG in vitro Dual IGF-1R/ErbB3 blocking enhanced chemosensitivity through inhibition of Akt phosphorylation and promotion of IGF-1R and ErbB3 degradation. Addition of istiratumab to gemcitabine and nab-paclitaxel improved chemotherapy activity in vivoConclusions: Our findings suggest a critical role for the HRG/ErbB3 axis and support the clinical exploration of dual IGF-1R/ErbB3 blocking in pancreatic Cancer. Clin Cancer Res; 24(12); 2873-85. ©2018 AACR.