VEGF blockade enhances the antitumor effect of BRAFV 600E inhibition

Valentina Comunanza, Davide Corà, Francesca Orso, Francesca Maria Consonni, Emanuele Middonti, Federica Di Nicolantonio, Anton Buzdin, Antonio Sica, Enzo Medico, Dario Sangiolo, Daniela Taverna, Federico Bussolino

Research output: Contribution to journalArticle

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 BRAFV 600E inhibitors with anti-angiogenic regimens.

Original languageEnglish
JournalEMBO Molecular Medicine
DOIs
Publication statusPublished - 2016

Keywords

  • Angiogenesis
  • Drug resistance
  • Extracellular matrix
  • Myeloid infiltration
  • Vascular normalization

ASJC Scopus subject areas

  • Molecular Medicine

Fingerprint Dive into the research topics of 'VEGF blockade enhances the antitumor effect of BRAF<sup>V</sup> <sup>600E</sup> inhibition'. Together they form a unique fingerprint.

Cite this