Format

Send to

Choose Destination
EMBO Mol Med. 2017 Feb;9(2):219-237. doi: 10.15252/emmm.201505774.

VEGF blockade enhances the antitumor effect of BRAFV600E inhibition.

Author information

1
Department of Oncology, University of Torino, Candiolo, Italy.
2
Candiolo Cancer Institute IRCCS, Candiolo, Italy.
3
Center for Molecular Systems Biology, University of Torino, Orbassano, Italy.
4
Molecular Biotechnology Center (MBC), Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
5
Humanitas Clinical and Research Center, Rozzano, Italy.
6
Laboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
7
National Research Centre "Kurchatov Institute", Centre for Convergence of Nano-, Bio-, Information and Cognitive Sciences and Technologies, Moscow, Russia.
8
Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", Novara, Italy.
9
Department of Oncology, University of Torino, Candiolo, Italy federico.bussolino@unito.it.

Abstract

The development of resistance remains a major obstacle to long-term disease control in cancer patients treated with targeted therapies. In BRAF-mutant mouse models, we demonstrate that although targeted inhibition of either BRAF or VEGF initially suppresses the growth of BRAF-mutant tumors, combined inhibition of both pathways results in apoptosis, long-lasting tumor responses, reduction in lung colonization, and delayed onset of acquired resistance to the BRAF inhibitor PLX4720. As well as inducing tumor vascular normalization and ameliorating hypoxia, this approach induces remodeling of the extracellular matrix, infiltration of macrophages with an M1-like phenotype, and reduction in cancer-associated fibroblasts. At the molecular level, this therapeutic regimen results in a de novo transcriptional signature, which sustains and explains the observed efficacy with regard to cancer progression. Collectively, our findings offer new biological rationales for the management of clinical resistance to BRAF inhibitors based on the combination between BRAFV600E inhibitors with anti-angiogenic regimens.

KEYWORDS:

angiogenesis; drug resistance; extracellular matrix; myeloid infiltration; vascular normalization

PMID:
27974353
PMCID:
PMC5286370
DOI:
10.15252/emmm.201505774
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center