The Evolution of Acquired Resistance to BRAFV600E kinase inhibitor Is Sustained by IGF1-Driven Tumor Vascular Remodeling.
J Invest Dermatol
; 142(2): 445-458, 2022 02.
Article
em En
| MEDLINE
| ID: mdl-34358527
ABSTRACT
As a hallmark of cancer, angiogenesis plays a pivotal role in carcinogenesis. However, the correlation between angiogenesis and the evolution of BRAFV600E kinase inhibitorâacquired 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 BRAFV600E kinase inhibitor but also provided a potential therapeutic strategy for the prevention of tumor relapse in clinical application.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Cutâneas
/
Fator de Crescimento Insulin-Like I
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Protocolos de Quimioterapia Combinada Antineoplásica
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Melanoma
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Recidiva Local de Neoplasia
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
/
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article