Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma

J Clin Invest. 2014 Apr;124(4):1582-6. doi: 10.1172/JCI72763. Epub 2014 Feb 24.

Abstract

Targeted cancer therapies often induce "outlier" responses in molecularly defined patient subsets. One patient with advanced-stage lung adenocarcinoma, who was treated with oral sorafenib, demonstrated a near-complete clinical and radiographic remission for 5 years. Whole-genome sequencing and RNA sequencing of primary tumor and normal samples from this patient identified a somatic mutation, ARAF S214C, present in the cancer genome and expressed at high levels. Additional mutations affecting this residue of ARAF and a nearby residue in the related kinase RAF1 were demonstrated across 1% of an independent cohort of lung adenocarcinoma cases. The ARAF mutations were shown to transform immortalized human airway epithelial cells in a sorafenib-sensitive manner. These results suggest that mutant ARAF is an oncogenic driver in lung adenocarcinoma and an indicator of sorafenib response.

Publication types

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

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / enzymology
  • Adenocarcinoma / genetics*
  • Adenocarcinoma of Lung
  • Aged
  • Amino Acid Substitution
  • Antineoplastic Agents / therapeutic use*
  • Cell Transformation, Neoplastic / genetics
  • DNA, Neoplasm / genetics
  • Female
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / genetics*
  • Molecular Targeted Therapy
  • Mutation, Missense*
  • Niacinamide / analogs & derivatives*
  • Niacinamide / therapeutic use
  • Oncogenes
  • Phenylurea Compounds / therapeutic use*
  • Proto-Oncogene Proteins A-raf / genetics*
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins c-raf / genetics
  • Sorafenib

Substances

  • Antineoplastic Agents
  • DNA, Neoplasm
  • Phenylurea Compounds
  • Niacinamide
  • Sorafenib
  • BRAF protein, human
  • Proto-Oncogene Proteins A-raf
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-raf