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

• Published in: Clinical cancer research Vol. 24; no. 12; pp. 2873 - 2885
• Main Authors: Camblin, Adam J, Pace, Emily A, Adams, Sharlene, Curley, Michael D, Rimkunas, Victoria, Nie, Lin, Tan, Gege, Bloom, Troy, Iadevaia, Sergio, Baum, Jason, Minx, Charlene, Czibere, Akos, Louis, Chrystal U, Drummond, Daryl C, Nielsen, Ulrik B, Schoeberl, Birgit, Pipas, J Marc, Straubinger, Robert M, Askoxylakis, Vasileios, Lugovskoy, Alexey A
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 15.06.2018
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Apoptosis; Bispecific antibodies; Cancer; Cell survival; Chemotherapy; Design factors; Design standards; ErbB-3 protein; Experimental design; Gemcitabine; Growth factors; Heregulin; In vivo methods and tests; Inhibition; Insulin; Insulin-like growth factor I; Insulin-like growth factor I receptors; Insulin-like growth factors; Paclitaxel; Pancreatic cancer; Phosphorylation; Receptors; Screening; Signaling; Tumor cell lines; Xenografts; Xenotransplantation
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-17-2262

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. 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 chemotherapy activity in pancreatic cancer xenograft models were determined. 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 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 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. .