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The evolution of acquired resistance to BRAF inhibitor is sustained by IGF1-driven tumor vascular remodeling.

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机构： [1]Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China. [2]Department of Thyroid and Parathyroid Surgery Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. [3]Core Facility of West China Hospital, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. [4]State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China. [5]College of Pharmacy and Biological Engineering, Sichuan Industrial Institute of Antibiotics, Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Chengdu University, Chengdu, Sichuan 610106, China.

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As hallmark of cancer, angiogenesis plays a pivotal role in carcinogenesis. The correlation between angiogenesis and evolution of BRAF inhibitor acquired resistance is, however, still poorly understood. Here, we reported that the molecular signatures of angiogenesis were enriched in early on-treated biopsies but not in disease progressed biopsies. The process of drug resistance development was accompanied by remodeling of vascular morphology, which was potentially manipulated by tumor-secreted pro-angiogenic factors. Further transcriptomic dissection indicated that tumor-secreted IGF1 drove the vascular remodeling through activating IGF1/IGF1R axis on endothelial cells, and sustained the prompt re-growth of resistant tumor. Blockade of IGF1R with small molecules at early stage of response disrupted vascular reconstruction, and subsequently delayed tumor relapse. Our findings not only demonstrated the correlation between IGF1-mediated tumor vascular remodeling and the development of acquired resistance to BRAFi but also provided a potential therapeutic strategy for the prevention of tumor relapse in clinical application.Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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出版当年[2021]版：

大类 | 1 区

医学

小类 | 1 区皮肤病学

最新[2023]版：

大类 | 2 区

医学

小类 | 2 区皮肤病学

第一作者：

第一作者机构： [1]Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China.

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通讯机构： [1]Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China. [*1]Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China

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