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

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.

PMID:
24569458
PMCID:
PMC3973082
DOI:
10.1172/JCI72763
[Indexed for MEDLINE]
Free PMC Article

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