The Evolution of Acquired Resistance to BRAFV600E kinase inhibitor Is Sustained by IGF1-Driven Tumor Vascular Remodeling

Abstract

As a hallmark of cancer, angiogenesis plays a pivotal role in carcinogenesis. However, the correlation between angiogenesis and the evolution of BRAF^V600E kinase inhibitor‒acquired resistance is still poorly understood. In this study, 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 the remodeling of vascular morphology, which was potentially manipulated by tumor-secreted proangiogenic factors. Further transcriptomic dissection indicated that tumor-secreted IGF1 drove the vascular remodeling by activating the IGF1/IGF1R axis on endothelial cells and sustained the prompt regrowth of resistant tumor. Blockade of IGF1R with small molecules at an early stage of response disrupted vascular reconstruction and subsequently delayed tumor relapse. Our findings not only showed the correlation between IGF1-mediated tumor vascular remodeling and the development of acquired resistance to BRAF^V600E kinase inhibitor but also provided a potential therapeutic strategy for the prevention of tumor relapse in clinical application.