Abstract C139: Oncogenic ARAF mutation in a metastatic lung adenocarcinoma from a patient exhibiting sustained sorafenib response.

Abstract

Abstract Targeted cancer therapies often induce "outlier" responses in molecularly defined patient subsets. One patient with advanced-stage lung adenocarcinoma who was treated with sorafenib demonstrated a near-complete clinical and radiographic remission for five years. Whole-genome sequencing and RNA sequencing on primary tumor and normal samples from this patient identified a somatic mutation, encoding ARAF S214C, present in the cancer genome and expressed at high levels. ARAF S214 binds 14-3-3 proteins when phosphorylated, and, by analogy to the paralogous residue of RAF1, presumably interferes with binding of ARAF to activated Ras. Mutation of S214 impaired the ability of ARAF to bind 14-3-3ξ, likely contributing to the oncogenic activity of ARAF S214C. 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 and RAF1 mutants transformed immortalized human airway epithelial cells and were associated with in vitro sorafenib sensitivity. These results suggest that mutant ARAF may be a novel oncogenic driver in lung adenocarcinoma and an indicator of sorafenib response. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C139. Citation Format: Heidi E. Greulich, Marcin Imielinski, Bethany Kaplan, Luiz Araujo, Joseph Amann, Leora Horn, Miguel Villalona, Matthew Meyerson, David Carbone. Oncogenic ARAF mutation in a metastatic lung adenocarcinoma from a patient exhibiting sustained sorafenib response. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C139.