Oncogene mimicry as a mechanism of primary resistance to BRAF inhibitors

Cell Rep. 2014 Aug 21;8(4):1037-48. doi: 10.1016/j.celrep.2014.07.010. Epub 2014 Aug 7.

Abstract

Despite the development of potent RAF/mitogen-activated protein kinase (MAPK) pathway inhibitors, only a fraction of BRAF-mutant patients benefit from treatment with these drugs. Using a combined chemogenomics and chemoproteomics approach, we identify drug-induced RAS-RAF-MEK complex formation in a subset of BRAF-mutant cancer cells characterized by primary resistance to vemurafenib. In these cells, autocrine interleukin-6 (IL-6) secretion may contribute to the primary resistance phenotype via induction of JAK/STAT3 and MAPK signaling. In a subset of cell lines, combined IL-6/MAPK inhibition is able to overcome primary resistance to BRAF-targeted therapy. Overall, we show that the signaling plasticity exerted by primary resistant BRAF-mutant cells is achieved by their ability to mimic signaling features of oncogenic RAS, a strategy that we term "oncogene mimicry." This model may guide future strategies for overcoming primary resistance observed in these tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Autocrine Communication
  • Benzamides / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Diphenylamine / analogs & derivatives*
  • Diphenylamine / pharmacology
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Humans
  • Interleukin-6 / metabolism
  • MAP Kinase Signaling System
  • Mice, Nude
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Mutation, Missense
  • Niacinamide / analogs & derivatives*
  • Niacinamide / pharmacology
  • Oncogenes*
  • Phenylurea Compounds / pharmacology*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / genetics
  • Sorafenib
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Benzamides
  • IL6 protein, human
  • Interleukin-6
  • PD 0325901
  • Phenylurea Compounds
  • Niacinamide
  • Diphenylamine
  • Sorafenib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Mitogen-Activated Protein Kinases