Comparative profiles of BRAF inhibitors: the paradox index as a predictor of clinical toxicity

Oncotarget. 2016 May 24;7(21):30453-60. doi: 10.18632/oncotarget.8351.


BRAF inhibitor (BRAFi) therapy is associated with the induction of neoplasia, most commonly cutaneous squamous cell carcinoma (cuSCC). This toxicity is explained in part by "paradoxical ERK activation," or the hyperactivation of ERK signaling by BRAFi in BRAF wild-type cells. However, the rate of cuSCC induction varies widely among BRAFi. To explore this mechanistically, we profiled paradoxical ERK activation by vemurafenib, dabrafenib, encorafenib (LGX818), and PLX8394, demonstrating that vemurafenib induces ERK activation the greatest, while dabrafenib and encorafenib have higher "paradox indices", defined as the pERK activation EC80 divided by the IC80 against A375, corresponding to wider therapeutic windows for achieving tumor inhibition without paradoxical ERK activation. Our results identify differences in the paradox indices of these compounds as a potential mechanism for the differences in cuSCC induction rates and highlight the utility of using ERK activity as a biomarker for maximizing the clinical utility of BRAFi.

Keywords: BRAF; melanoma; paradoxical ERK; small molecule inhibitor; squamous cell carcinoma.

Publication types

  • Comparative Study

MeSH terms

  • Apoptosis / drug effects
  • Carbamates / adverse effects
  • Carcinoma, Squamous Cell / chemically induced*
  • Cell Line
  • Cell Line, Tumor
  • Enzyme Activation / drug effects
  • Heterocyclic Compounds, 2-Ring / adverse effects
  • Humans
  • Imidazoles / adverse effects
  • Indoles / adverse effects
  • MAP Kinase Signaling System / drug effects*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Oximes / adverse effects
  • Protein Kinase Inhibitors / adverse effects*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Skin Neoplasms / chemically induced*
  • Sulfonamides / adverse effects
  • Vemurafenib


  • Carbamates
  • Heterocyclic Compounds, 2-Ring
  • Imidazoles
  • Indoles
  • Oximes
  • PLX8394
  • Protein Kinase Inhibitors
  • Sulfonamides
  • Vemurafenib
  • encorafenib
  • Proto-Oncogene Proteins B-raf
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • dabrafenib