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

ABSTRACT 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.