Targeting oncogenic serine/threonine-protein kinase BRAF in cancer cells inhibits angiogenesis and abrogates hypoxia

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-02, Vol.109 (6), p.1836-1837
• Main Authors: Bottos, Alessia, Martini, Miriam, Di Nicolantonio, Federica, Comunanza, Valentina, Maione, Federica, Minassi, Alberto, Appendino, Giovanni, Bussolino, Federico, Bardelli, Alberto
• Format: Article
• Language: English
• Subjects: Alleles; Angiogenesis; Angiogenesis Inducing Agents - metabolism; Animals; Antibodies, Monoclonal, Humanized - pharmacology; Bevacizumab; Biological Sciences; Blood Vessels - drug effects; Blood Vessels - pathology; Cancer; Carcinoma; Cell Hypoxia - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cells; Chickens; Chorioallantoic Membrane - blood supply; Chorioallantoic Membrane - drug effects; Cytostatic Agents - pharmacology; Down-Regulation - drug effects; Epithelial cells; Extracellular signal-regulated kinase; Gene Knock-In Techniques; Genomes; Humans; Hypoxia; Indoles - pharmacology; Kinases; MAP Kinase Signaling System - drug effects; Mice; Molecular Targeted Therapy; Mutation - genetics; Necrosis; Neoplasms - blood supply; Neoplasms - enzymology; Neoplasms - pathology; Neovascularization, Pathologic - enzymology; Neovascularization, Pathologic - pathology; Oncogenes; PNAS Plus; PNAS PLUS (AUTHOR SUMMARIES); Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Stroma; Sulfonamides - pharmacology; Tumor cells; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1105026109

Carcinomas are comprised of transformed epithelial cells that are supported in their growth by a dedicated neovasculature. How the genetic milieu of the epithelial compartment influences tumor angiogenesis is largely unexplored. Drugs targeted to mutant cancer genes may act not only on tumor cells but also, directly or indirectly, on the surrounding stroma. We investigated the role of the BRAF V600E oncogene in tumor/vessel crosstalk and analyzed the effect of the BRAF inhibitor PLX4720 on tumor angiogenesis. Knock-in of the BRAF V600E allele into the genome of human epithelial cells triggered their angiogenic response. In cancer cells harboring oncogenic BRAF, the inhibitor PLX4720 switches off the ERK pathway and inhibits the expression of proangiogenic molecules. In tumor xenografts harboring the BRAF V600E , PLX4720 extensively modifies the vascular network causing abrogation of hypoxia. Overall, our results provide a functional link between oncogenic BRAF and angiogenesis. Furthermore, they indicate how the tumor vasculature can be “indirectly” besieged through targeting of a genetic lesion to which the cancer cells are addicted.