Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer

Activation of MAPK signaling via BRAF mutations may limit the activity of EGFR inhibitors in EGFR-mutant lung cancer patients. However, the impact of BRAF mutations on the selection and fitness of emerging resistant clones during anti-EGFR therapy remains elusive. We tracked the evolution of subclonal mutations by whole-exome sequencing and performed clonal analyses of individual metastases during therapy. Complementary functional analyses of polyclonal EGFR-mutant cell pools showed a dose-dependent enrichment of BRAF(V600E) and a loss of EGFR inhibitor susceptibility. The clones remain stable and become vulnerable to combined EGFR, RAF, and MEK inhibition. Moreover, only osimertinib/trametinib combination treatment, but not monotherapy with either of these drugs, leads to robust tumor shrinkage in EGFR-driven xenograft models harboring BRAF mutations. These data provide insights into the dynamics of clonal evolution of EGFR-mutant tumors and the therapeutic implications of BRAF(V600E) co-mutations that may facilitate the development of treatment strategies to improve the prognosis of these patients

Abundance of LRP12 C-rs9694676 allelic promoter variant in epilepsy-associated gangliogliomas

Aims: Chronic epilepsy associated gangliogliomas (GGs) represent tumors composed of irregularly distributed, often dysmorphic, neurons and neoplastic astroglia. The pathogenesis of GGs is largely unknown. Low-density lipoprotein receptor-related protein 12 (LRP12) is critical for brain development and involved in tumorigenesis of non-cerebral neoplasms. Main methods: Here, we have examined a potential role of LRP12 in the pathogenesis of GGs by a combination of mRNA quantification and molecular-biological in vitro assays. Key findings: We observed a significant increase of the single nucleotide polymorphism(SNP) rs9694676 C-allele, located in the LRP12 promoter, in GGs compared to normal control individuals. C-allele expression is correlated with abundant seizure frequency. Expression of LRP12 was lower in GGs than in control brain. In luciferase assays, the C-allele of rs9694676 decreases both, the basal LRP12 core promoter activity and the stimulatory effect of the transcription factor (TF) STAT5a. Significance: Accumulation of functional promoter-associated allelic variants with impact on the transcriptional regulation of LRP12 provides a new pathomechanism for GGs, i.e. highly differentiated epileptogenic brain tumors. (C) 2016 Elsevier Inc. All rights reserved