Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma

Marcin Imielinski, Heidi Greulich, Bethany Kaplan, Luiz Araujo, Joseph Amann, Leora Horn, Joan Schiller, Miguel A. Villalona-Calero, Matthew Meyerson, David P. Carbone

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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.

Original languageEnglish (US)
Pages (from-to)1582-1586
Number of pages5
JournalJournal of Clinical Investigation
Volume124
Issue number4
DOIs
StatePublished - Apr 1 2014

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Imielinski, M., Greulich, H., Kaplan, B., Araujo, L., Amann, J., Horn, L., Schiller, J., Villalona-Calero, M. A., Meyerson, M., & Carbone, D. P. (2014). Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma. Journal of Clinical Investigation, 124(4), 1582-1586. https://doi.org/10.1172/JCI72763