Vemurafenib Induces Senescence Features in Melanoma Cells

J Invest Dermatol. 2013 Jun;133(6):1601-9. doi: 10.1038/jid.2013.6. Epub 2013 Feb 14.

Abstract

A large proportion of human melanomas harbor a mutation leading to permanent activation of the serine/threonine kinase BRAF, and as a consequence, they have developed dependence on BRAF/mitogen-activated protein kinase signaling. Accordingly, BRAF inhibitors such as Vemurafenib show a good anti-tumorigenic effect on metastases with the BRAF(V600E) mutation. Although an initial period of sustained tumor regression is usually observed after Vemurafenib treatment, tumors often relapse at the same site, and apoptosis induction of melanoma cells in vitro is incomplete. Here, we demonstrate, using a large panel of melanoma cell lines, that Vemurafenib induces features of stress-induced senescence in addition to apoptosis. This senescence phenotype is characterized by heterochromatin formation, changes in cell shape, and increased senescence-associated β-galactosidase activity. Importantly, senescence features induced by BRAF(V600E) inhibition was also detected in human melanoma cells xenografted into nude mice. Our observations provide a possible explanation for the lack of complete and durable pro-apoptotic effect of Vemurafenib in patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cellular Senescence / drug effects*
  • Disease Models, Animal
  • Female
  • Humans
  • Indoles / pharmacology*
  • MAP Kinase Signaling System / drug effects
  • Melanoma / drug therapy*
  • Melanoma / pathology
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / pathology
  • Sulfonamides / pharmacology*
  • Vemurafenib
  • Xenograft Model Antitumor Assays

Substances

  • Indoles
  • Sulfonamides
  • Vemurafenib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf