Cooperation of BRAFF595L and mutant HRAS in histiocytic sarcoma provides new insights into oncogenic BRAF signaling

Abstract

Activating BRAF mutations, in particular V600E/K, drive many cancers and are considered mutually exclusive with mutant RAS, whereas inactivating BRAF mutations in the D(594)F(595)G(596) motif cooperate with RAS via paradoxical MEK/ERK activation. Due to the increasing use of comprehensive tumor genomic profiling, many non-V600 BRAF mutations are being detected whose functional consequences and therapeutic actionability are often unknown. We investigated an atypical BRAF mutation, F595L, which was identified along with mutant HRAS in histiocytic sarcoma and also occurs in epithelial cancers, melanoma and neuroblastoma, and determined its interaction with mutant RAS. Unlike other DFG motif mutants, BRAF(F595L) is a gain-of-function variant with intermediate activity that does not act paradoxically, but nevertheless cooperates with mutant RAS to promote oncogenic signaling, which is efficiently blocked by pan-RAF and MEK inhibitors. Mutation data from patients and cell lines show that BRAF(F595L), as well as other intermediate-activity BRAF mutations, frequently coincide with mutant RAS in various cancers. These data define a distinct class of activating BRAF mutations, extend the spectrum of patients with systemic histiocytoses and other malignancies who are candidates for therapeutic blockade of the RAF-MEK-ERK pathway and underscore the value of comprehensive genomic testing for uncovering the vulnerabilities of individual tumors.

Integration of genomics and histology revises diagnosis and enables effective therapy of refractory cancer of unknown primary with PDL1 amplification

“…In an attempt to refine the diagnosis and inform potential therapeutic strategies, the patient was enrolled in NCT (Nationales Centrum für Tumorerkrankungen) MASTER (Molecularly Aided Stratification for Tumor Eradication Research), a cross-entity molecular stratification program for younger adults with advanced-stage cancer and patients with rare tumors (Kordes et al 2016), and a cryopreserved biopsy of a metastatic shoulder lesion with a tumor cell content of >90% was analyzed by WES and RNA-seq. Peripheral blood mononuclear cells served as a germline control.…”

“…Hence, responses can be difficult to predict, particularly to drugs not developed for a given indication (Le Tourneau et al 2015). Despite this purported predicament, targeted therapies have become the mainstay of treatment in a range of malignancies (e.g., gastrointestinal stromal tumor, chronic myeloid leukemia, or non-small-cell lung cancer), underscoring the utility of personalized genomic medicine and the incorporation of “omics” data in the clinical decision algorithm on an individual-case basis in patients otherwise refractory to conventional treatment modalities (Tothill et al 2013; Knoechel et al 2015; Schwaederle et al 2015; Kordes et al 2016). Our diagnostic approach ruled out sarcoma and rendered the diagnosis of poorly differentiated adenocarcinoma.…”

“…Paired-end sequencing (2 × 101 bp) was performed with a HiSeq 2500 instrument (Illumina) in a rapid mode. Sequencing data were analyzed using a previously reported bioinformatics workflow (Kordes et al 2016; see Table 2 for coverage metrics).…”

Evolution of a FLT3-TKD mutated subclone at meningeal relapse in acute promyelocytic leukemia

“…High-throughput sequencing and data analysis were performed as described (Kordes et al 2016). In brief, exome capturing was performed using SureSelect Human All Exon V5+UTRs in-solution capture reagents (Agilent).…”

Genetic Profiling of Cancers of the Digestive System: Biological Insights and Clinical Implications

“…Third, multigene testing for deselection of patients who will not benefit from a specific therapy has been shown to be cost-effective even in the setting of high test costs [73] . Finally, nowadays a variety of novel precision medicine approaches specifically aim to broadly stratifying patients to as yet nonapproved drugs/drug combinations as a final rescue attempt [74] . This applies in particular to last-line therapy settings in common tumor entities and to patients with rare tumors without firmly established therapy regimens.…”