RESUMO
BRAF mutations are found in 1-5% of non-small-cell lung cancer (NSCLC), with V600 and non-V600 accounting for approximately 50% each. It has been confirmed that targeted therapy with dabrafenib + trametinib is effective in patients with metastatic NSCLC carrying BRAF V600E mutations. Preclinical studies have shown that dabrafenib + trametinib may also have inhibitory effects on some types of non-V600E mutations, especially some class II BRAF mutations. However, the efficacy of dabrafenib + trametinib on non-V600E mutant NSCLC in clinical practice only exists in some case reports. Here, we report a case of NSCLC patient carrying BRAF ex15 p.T599dup, who showed a clinical response to the combined therapy of dabrafenib + trametinib.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Imidazóis , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Oximas/uso terapêutico , Mutação , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/uso terapêuticoRESUMO
In this study, we tested the hypothesis that extracellular vesicles (EVs)-mediated transfer of miR-208a/b can exacerbate apoptosis of cardiomyocytes (CMs) induced by hypoxia/reoxygenation (H/R) injury by reducing the expression of the RNA-binding protein Quaking (QKI). EVs were isolated from culture medium of hypoxic H9c2 cells (EVs-H). In in vitro H9c2 cell model, the EVs-H could be taken up by normoxic CMs and exacerbated cell apoptosis induced by H/R injury. In addition, miR-208a and miR-208b were enriched in EVs-H. Suppression of miR-208a and miR-208b loading significantly suppressed the detrimental effect of EVs-H on H/R injury in H9c2 cells. Inhibition of endogenous miR-208a and miR-208b restored QKI5 and QKI6 after H/R treatment. Dual-luciferase assay confirmed direct bindings between miR-208a/b and QKI 3'UTR. Functionally, QKI5 overexpression significantly suppressed H/R-induced CM apoptosis and suppressed the enhancing effect of EVs-H on CM apoptosis. Therefore, we infer that EVs-mediated transfer of miR-208a/b can exaggerate H/R injury in CMs by reducing QKI expression. This represents a previously unrecognized pathway of H/R injury in CMs.
