Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 124, Issue 4, Pages 1582-1586Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI72763
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Funding
- NCI [T32 CA9216-31, U01CA114771]
- Conquer Cancer Foundation of ASCO Long-Term International Fellowship
- Uniting Against Lung Cancer
- Lung Cancer Research Foundation
- Novartis
- Department of Defense Congressionally Directed Medical Research Programs Lung Cancer Research Program [W81XWH-12-1-0269]
- American Lung Association
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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.
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