Xingxing Yao1, Zhanke He1, Caolitao Qin2, Penghao Zhang1, Chuyang Sui1, Xiangqian Deng1, Yuxin Fang3, Guoxin Li4, Jiaolong Shi5. 1. Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, China. 2. Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases & Department of Radiation Oncology, The Sixth Affiliated Hospital of Sun Yat-sen University, 510655, Guangzhou, China. 3. Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China. 4. Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, China. gzliguoxin@163.com. 5. Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, China. shijiaolong10@smu.edu.cn.
Abstract
BACKGROUND: Multiple mechanisms have been proposed that lead to reduced effectiveness of trastuzumab in HER2-positive gastric cancer (GC), yet resistance to trastuzumab remains a challenge in clinics. METHODS: We established trastuzumab-resistant cells and patient-derived xenografts models to measure metabolic levels and vascular density and shape. The HER2-positive GC patient samples were used to determine clinical significance. We also measured protein expression and phosphorylation modifications to determine those alterations related to resistance. In vivo studies combining inhibitor of PFKFB3 with trastuzumab corroborated the in vitro findings. RESULTS: The 6-phosphofructo-2-kinase (PFKFB3)-mediated trastuzumab resistance pathways in HER2-positive GC by activating the glycolytic pathway. We also found vessels are chaotic and destabilised in the tumour during the trastuzumab resistance process. Inhibition of PFKFB3 significantly diminished tumour proliferation and promoted vessel normalisation in the patient-derived xenograft model. Mechanistically, PFKFB3 promoted the secretion of CXCL8 into the tumour microenvironment, and phosphorylated Ser1151 of ERBB2, enhancing the transcription of CXCL8 by activating the PI3K/AKT/NFκB p65 pathway. CONCLUSIONS: Our current findings discover that PFKFB3 inhibitors might be effective tools to overcome adjuvant therapy resistance in HER2-positive GC and reshaping the microenvironment by normalising tumour vessels is a novel strategy to overcome trastuzumab resistance.
BACKGROUND: Multiple mechanisms have been proposed that lead to reduced effectiveness of trastuzumab in HER2-positive gastric cancer (GC), yet resistance to trastuzumab remains a challenge in clinics. METHODS: We established trastuzumab-resistant cells and patient-derived xenografts models to measure metabolic levels and vascular density and shape. The HER2-positive GC patient samples were used to determine clinical significance. We also measured protein expression and phosphorylation modifications to determine those alterations related to resistance. In vivo studies combining inhibitor of PFKFB3 with trastuzumab corroborated the in vitro findings. RESULTS: The 6-phosphofructo-2-kinase (PFKFB3)-mediated trastuzumab resistance pathways in HER2-positive GC by activating the glycolytic pathway. We also found vessels are chaotic and destabilised in the tumour during the trastuzumab resistance process. Inhibition of PFKFB3 significantly diminished tumour proliferation and promoted vessel normalisation in the patient-derived xenograft model. Mechanistically, PFKFB3 promoted the secretion of CXCL8 into the tumour microenvironment, and phosphorylated Ser1151 of ERBB2, enhancing the transcription of CXCL8 by activating the PI3K/AKT/NFκB p65 pathway. CONCLUSIONS: Our current findings discover that PFKFB3 inhibitors might be effective tools to overcome adjuvant therapy resistance in HER2-positive GC and reshaping the microenvironment by normalising tumour vessels is a novel strategy to overcome trastuzumab resistance.
Authors: Valentina Gambardella; Francisco Gimeno-Valiente; Josefa Castillo; Andrés Cervantes; Noelia Tarazona; Carolina Martinez-Ciarpaglini; Desamparados Roda; Tania Fleitas; Pablo Tolosa; Juan Miguel Cejalvo; Marisol Huerta; Susana Roselló Journal: Clin Cancer Res Date: 2018-11-30 Impact factor: 12.531
Authors: Peter C Thuss-Patience; Manish A Shah; Atsushi Ohtsu; Eric Van Cutsem; Jaffer A Ajani; Hugo Castro; Wasat Mansoor; Hyun Cheol Chung; Gyorgy Bodoky; Kohei Shitara; Gail D Lewis Phillips; Tina van der Horst; Marie-Laurence Harle-Yge; Betsy L Althaus; Yoon-Koo Kang Journal: Lancet Oncol Date: 2017-03-23 Impact factor: 41.316