title: Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma.
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.
authors.forename: Marcin
authors.initials: M
authors.lastname: Imielinski
authors.forename: Heidi
authors.initials: H
authors.lastname: Greulich
authors.forename: Bethany
authors.initials: B
authors.lastname: Kaplan
authors.forename: Luiz
authors.initials: L
authors.lastname: Araujo
authors.forename: Joseph
authors.initials: J
authors.lastname: Amann
authors.forename: Leora
authors.initials: L
authors.lastname: Horn
authors.forename: Joan
authors.initials: J
authors.lastname: Schiller
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Villalona-Calero
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: David P
authors.initials: DP
authors.lastname: Carbone
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000368:Aged; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D058990:Molecular Targeted Therapy; D020125:Mutation, Missense; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009857:Oncogenes; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D048491:Proto-Oncogene Proteins A-raf / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; C482119:BRAF protein, human; D048491:Proto-Oncogene Proteins A-raf; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf