Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts.
Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York.
Clin Cancer Res. 2018 Jun 15;24(12):2873-2885. doi: 10.1158/1078-0432.CCR-17-2262. Epub 2018 Mar 16.
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. .
胰岛素样生长因子受体 1（IGF-1R）在胰腺癌病理生理学中起着至关重要的作用，促进癌细胞存活和治疗耐药性。然而，评估 IGF-1R 抑制剂与标准护理化疗联合应用并未显示出显著的临床获益。本研究旨在揭示胰腺癌对 IGF-1R 抑制的耐药机制，并开发提高标准护理疗法活性的新策略。在胰腺癌细胞系中进行生长因子筛选，以鉴定促进生存的 PI3K/AKT 信号的激活剂。评估胰腺癌患者样本中激活生长因子及其受体的普遍性。在胰腺癌细胞异种移植模型中，测定双特异性 IGF-1R 和 ErbB3 靶向抗体对受体表达、信号转导、癌细胞活力和凋亡、球体生长以及化疗活性的影响。在胰腺癌细胞中进行生长因子筛选，发现胰岛素样生长因子 1（IGF-1）和人表皮生长因子受体 3（HER3）是最有效的 AKT 激活剂。这两种生长因子均降低了球体生长试验中胰腺癌细胞对吉西他滨或紫杉醇的敏感性。Istiratumab（MM-141）是一种新型双特异性抗体，可阻断 IGF-1R 和 ErbB3，在存在 IGF-1 和 HRG 的情况下恢复紫杉醇和吉西他滨的活性。双 IGF-1R/ErbB3 阻断通过抑制 AKT 磷酸化和促进 IGF-1R 和 ErbB3 降解增强化疗敏感性。将 istiratumab 与吉西他滨和 nab-紫杉醇联合使用可提高化疗活性。我们的研究结果表明 HRG/ErbB3 轴在胰腺癌中起着关键作用，并支持在胰腺癌中探索双 IGF-1R/ErbB3 阻断的临床应用。
