TY - JOUR
T1 - VEGF blockade enhances the antitumor effect of BRAFV 600E inhibition
AU - Comunanza, Valentina
AU - Corà, Davide
AU - Orso, Francesca
AU - Consonni, Francesca Maria
AU - Middonti, Emanuele
AU - Di Nicolantonio, Federica
AU - Buzdin, Anton
AU - Sica, Antonio
AU - Medico, Enzo
AU - Sangiolo, Dario
AU - Taverna, Daniela
AU - Bussolino, Federico
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Angiogenesis
KW - Drug resistance
KW - Extracellular matrix
KW - Myeloid infiltration
KW - Vascular normalization
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U2 - 10.15252/emmm.201505774
DO - 10.15252/emmm.201505774
M3 - Article
AN - SCOPUS:85007170690
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
ER -