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Dual Inhibition of IGF-1R and Erbb3 Enhances the Activity of Gemcitabine and Nab-Paclitaxel in Preclinical Models of Pancreatic Cancer Adam J

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Dual Inhibition of IGF-1R and Erbb3 Enhances the Activity of Gemcitabine and Nab-Paclitaxel in Preclinical Models of Pancreatic Cancer Adam J Published OnlineFirst March 16, 2018; DOI: 10.1158/1078-0432.CCR-17-2262 Cancer Therapy: Preclinical Clinical Cancer Research Dual Inhibition of IGF-1R and ErbB3 Enhances the Activity of Gemcitabine and Nab-Paclitaxel in Preclinical Models of Pancreatic Cancer Adam J. Camblin1, Emily A. Pace1, Sharlene Adams1, Michael D. Curley1, Victoria Rimkunas1, Lin Nie1,GegeTan1, Troy Bloom1, Sergio Iadevaia1, Jason Baum1, Charlene Minx2, Akos Czibere1, Chrystal U. Louis1, Daryl C. Drummond1, Ulrik B. Nielsen1, Birgit Schoeberl1, J. Marc Pipas1, Robert M. Straubinger2,3, Vasileios Askoxylakis1, and Alexey A. Lugovskoy1 Abstract Purpose: Insulin-like growth factor receptor 1 (IGF-1R) is and apoptosis, spheroid growth, and in vivo chemotherapy activity critically involved in pancreatic cancer pathophysiology, promot- in pancreatic cancer xenograft models were determined. ing cancer cell survival and therapeutic resistance. Assessment of Results: Growth factor screening in pancreatic cancer cells IGF-1R inhibitors in combination with standard-of-care chemo- revealed insulin-like growth factor 1 (IGF-1) and heregulin therapy, however, failed to demonstrate significant clinical ben- (HRG) as the most potent AKT activators. Both growth factors efit. The aim of this work is to unravel mechanisms of resistance reduced pancreatic cancer cell sensitivity to gemcitabine or to IGF-1R inhibition in pancreatic cancer and develop novel paclitaxel in spheroid growth assays. Istiratumab (MM-141), strategies to improve the activity of standard-of-care therapies. a novel bispecific antibody that blocks IGF-1R and ErbB3, Experimental Design: Growth factor screening in pancreatic restored the activity of paclitaxel and gemcitabine in the pre- cancer cell lines was performed to identify activators of prosurvi- sence of IGF-1 and HRG in vitro. Dual IGF-1R/ErbB3 blocking val PI3K/AKT signaling. The prevalence of activating growth enhanced chemosensitivity through inhibition of AKT phos- factors and their receptors was assessed in pancreatic cancer phorylation and promotion of IGF-1R and ErbB3 degradation. patient samples. Effects of a bispecific IGF-1R and ErbB3 targeting Addition of istiratumab to gemcitabine and nab-paclitaxel antibody on receptor expression, signaling, cancer cell viability improved chemotherapy activity Clin Cancer Res; 1–13. Ó2018 AACR. Introduction 11.1 months, respectively (3, 4). Despite the largest increase in survival for FOLFIRINOX, this regimen is characterized by Pancreatic cancer remains a leading cause of cancer mortality substantial toxicity and is usually restricted to patients with (1). The 5-year overall survival (OS) rate for pancreatic ductal good performance status. Recently, nanoliposomal irinotecan adenocarcinoma (PDAC) is only 5% to 10% (2). The most (Onivyde), in combination with fluorouracil and leucovorin, effective first-line treatments for patients with metastatic dis- was approved by the US Food and Drug Administration for the ease include a combination of gemcitabine with nab-paclitaxel treatment of patients with metastatic disease who previously (3), and a four-drug combination, consisting of leucovorin, received gemcitabine-based therapy (5, 6). Although this com- fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX; ref. 4). bination extends survival and has a manageable safety profile, Median overall survival (mOS) with these regimens is 8.5 and mOS is 6.1 months (6). Therefore, there remains an urgent fi 1 2 need for novel therapies with better ef cacy to further improve Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts. Department of patient outcomes in this deadly neoplasm. Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York. 3Department of Pharmacology and Therapeutics, Roswell Park Compre- Insulin-like growth factor receptor 1 (IGF-1R) is a receptor hensive Cancer Center, Buffalo, New York. tyrosine kinase (RTK) that has a key role in cancer pathophysi- ology, promoting cancer cell survival and proliferation, tumor Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). growth, and therapeutic resistance (7, 8). Ligands of IGF-1R may be delivered through endocrine or autocrine/paracrine signaling A.J. Camblin, E.A. Pace, and S. Adams are equally contributing first authors. in aggressive cancers (9). Increased levels of insulin-like growth V. Askoxylakis and A.A. Lugovskoy are equally contributing senior authors. factor-1 (IGF-1) are associated with enhanced cancer risk and Corresponding Author: Adam J. Camblin, Merrimack Pharmaceuticals (United resistance to chemotherapies across multiple cancer indications; States), One Kendall Square, Building 700 Fl 2, Cambridge, MA 02139. Phone: including esophageal, colon, breast, prostate, and lung cancers 617-441-1000; Fax: 617-491-1386; E-mail: [email protected]; and (10–15). High levels of IGF-1 and IGF binding proteins have been Vasileios Askoxylakis, [email protected] detected in the blood of patients with pancreatic cancer, corre- doi: 10.1158/1078-0432.CCR-17-2262 lating with enhanced IGF-1R phosphorylation in tumor tissue Ó2018 American Association for Cancer Research. (16). High expression of IGF-1R in pancreatic cancer is associated www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst March 16, 2018; DOI: 10.1158/1078-0432.CCR-17-2262 Camblin et al. In vitro signaling experiments Translational Relevance Unless otherwise mentioned, cells were seeded into 96-well Metastatic pancreatic cancer remains a leading cause of tissue culture plates (Costar) at 20,000 cells/well in complete cancer mortality. High levels of IGF-1R in pancreatic cancer media supplemented with 10% FBS. The following day, cells were are associated with higher tumor grade and decreased survival. synchronized by 24-hour serum starvation in media with 2% FBS. However, IGF-1R inhibitors have failed to show significant Signaling experiments were stopped with a cold PBS wash, and clinical benefit. Our studies show that the HRG/ErbB3 axis is cell lysates were generated with Mammalian Protein Extraction critical to pancreatic cancer progression and therapeutic resis- Reagent (Thermo Scientific) supplemented with phosphatase and tance to IGF-1R inhibition. Both IGF-1R and ErbB3 can serve as protease inhibitor pellets (Roche) and 150 mmol/L sodium drivers of tumor growth and resistance/tolerance to standard- chloride (Sigma). For receptor ubiquitination experiments, cells of-care chemotherapy. Dual targeting of the IGF-1R and ErbB3 were seeded into 15 cm dishes, pretreated with the proteasome pathways with the novel bispecific antibody istiratumab inhibitor epoxomicin (Sigma) for 2 hours, and treated as indi- increases the activity of standard-of-care chemotherapies. cated. Cells were harvested and cell lysates clarified by centri- These data provide mechanistic insight into pancreatic cancer fugation at 13,000 rpm at 4C. Receptors were immediately resistance to IGF-1R inhibitors and identify novel translatable immunoprecipitated using Dynabeads (Life Technologies) with treatment strategies for the disease. IGF-1R (Cell Signaling Technology) or ErbB3 (R&D Systems) antibodies. For gemcitabine- and paclitaxel-induced upregulation of IGF-1R and ErbB3 receptors, cells were seeded into 10-cm dishes and lysates were clarified by centrifugation at 13,000 rpm with higher tumor grade and decreased survival (17). This pro- for 10 minutes at 4 C. vided the rationale for the development and clinical testing of Caspase-3/7 cleavage activity experiments IGF-1R inhibitors in pancreatic cancer. However, despite evidence Cells were seeded into 96-well tissue culture plates at 5,000 cells that IGF-1R pathway signaling is implicated in tumor progression, per well in media containing 2% FBS. The following day, media as well as promising early-phase clinical data with IGF-1R target- was replaced with media containing 2% FBS and the Essen ing antibodies (18, 19), larger phase III clinical trials failed to BioSciences IncuCyte Caspase-3/7 Green Apoptosis Assay Reagent show an advantage of targeting IGF-1R in pancreatic cancer (20). (catalog no. 4440), then immediately treated in octuplicate as Resistance to IGF-1R targeted therapies remains a major indicated. Caspase-3/7 activity was measured 16 hours following challenge. Mechanisms of resistance include a compensatory start of treatment in the IncuCyte imager, and then normalized re-activation of downstream PI3K/AKT/mTOR signaling to cell density within each well. (21). This hypothesis is supported by findings in various cancer types, which reveal an interplay between IGF-1R ELISA and other RTKs (22–25). Preclinical studies have shown that ELISAs were performed as described previously (17). Briefly, IGF-1R inhibition upregulates insulin receptor signaling in high-binding assay plates (Corning) were coated with capture malignancies (19, 21, 26), whereas further studies suggest antibodies and incubated overnight followed by blocking with that ErbB receptor signaling confers resistance to IGF-1R 2% BSA (Sigma) in PBS for 1 hour. Plates were incubated with inhibition (21, 23). lysate diluted 2-fold in 2% BSA, 0.1% Tween-20 PBS for 2 hours, Despite the well-characterized implications of IGF-1R sig- then with primary detection antibodies for 2 hours, followed by naling in pancreatic cancer, knowledge and understanding of secondary detection antibodies
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