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.

Cancer gene profiling in non-small cell lung cancers reveals activating mutations in JAK2 and JAK3 with therapeutic implications

“…Therefore, we ruled out the possibilities that the mutation is a technical or clinical artifact. Interestingly, although observed in three cases by an early study [45], the JAK2 p.V617F mutation was not identified in numerous whole-genome sequencing (WGS) or whole-exome sequencing (WES) studies of thousands of NSCLCs [5,[46][47][48][49][50]. One possible explanation is relatively low sequencing depth by WGS and WES for detection of mutations with low allele fractions.…”

Massive parallel sequencing uncovers actionable FGFR2–PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma

“…The N217I mutation is located in the regulatory region close to one of the known sites of phosphorylation and 14-3-3 binding (S214). Substitution of serine 214 by alanine (S214A) leads to an increased basal and inducible ARAF kinase activity when compared to the WT enzyme 34 . Similar results were also obtained with the homologous serine in BRAF (S365) indicating that the phosphorylation of this site and its interaction with 14-3-3 protein acts as a negative regulator of RAF activity 35 .…”

Clinicopathological examination of dipeptidase�1 expression in colorectal cancer

“…Sorafenib is one example of a drug that inhibits EMT via histone modifications that occur during EMT in lung adenocarcinoma cell lines (24). Currently, sorafenib is used for cases with an activating mutation of A-Raf proto-oncogene, serine/threonine kinase (25); with further research, sorafenib may be administered to CRC patients. In addition, an activating mutation in fibroblast growth factor receptor 4, which enhances EMT in colon cancer cells, is also hypothesized to be a therapeutic target of specific inhibitors for CRC (26,27).…”