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Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma
Marcin Imielinski, … , Matthew Meyerson, David P. Carbone
Marcin Imielinski, … , Matthew Meyerson, David P. Carbone
Published February 24, 2014
Citation Information: J Clin Invest. 2014;124(4):1582-1586. https://doi.org/10.1172/JCI72763.
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Brief Report Oncology

Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma

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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.

Authors

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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Figure 3

ARAF p.S214 mutations found in lung adenocarcinoma are oncogenic and sensitive to sorafenib.

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ARAF p.S214 mutations found in lung adenocarcinoma are oncogenic and se...
(A) Soft agar colony formation by AALE cells expressing variants of ARAF. pBp, empty vector; S214C and S214F, ARAF p.S214 variants; D429A, kinase-dead ARAF. (B) Immunoblot indicating protein levels and phosphorylation status of MEK. (C) Response of ARAF mutant AALE soft agar colony formation to the indicated concentrations of sorafenib. (D) Dose-response curves for data shown in C. Data and error bars in A, C, and D represent mean ± SEM, respectively, obtained from triplicate experiments.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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