RESUMO
BACKGROUND: Given the modest responses to everolimus, a mTOR inhibitor, in multiple tumor types, there is a pressing need to identify predictive biomarkers for this drug. Using targeted ultra-deep sequencing, we aimed to explore genomic alterations that confer extreme sensitivity to everolimus. RESULTS: We collected formalin-fixed paraffin-embedded tumor/normal pairs from 39 patients (22 with exceptional clinical benefit, 17 with no clinical benefit) who were treated with everolimus across various tumor types (13 gastric cancers, 15 renal cell carcinomas, 2 thyroid cancers, 2 head and neck cancer, and 7 sarcomas). Ion AmpliSeqTM Comprehensive Cancer Panel was used to identify alterations across all exons of 409 target genes. Tumors were sequenced to a median coverage of 552x. Cancer genomes are characterized by 219 somatic single-nucleotide variants (181 missense, 9 nonsense, 7 splice-site) and 22 frameshift insertions/deletions, with a median of 2.1 mutations per Mb (0 to 12.4 mutations per Mb). Overall, genomic alterations with activating effect on mTOR signaling were identified in 10 of 22 (45%) patients with clinical benefit and these include MTOR, TSC1, TSC2, NF1, PIK3CA and PIK3CG mutations. Recurrently mutated genes in chromatin remodeling genes (BAP1; n = 2, 12%) and receptor tyrosine kinase signaling (FGFR4; n = 2, 12%) were noted only in patients without clinical benefit. CONCLUSIONS: Regardless of different cancer types, mTOR-pathway-activating mutations confer sensitivity to everolimus. Targeted sequencing of mTOR pathway genes facilitates identification of potential candidates for mTOR inhibitors.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Everolimo/uso terapêutico , Aparelho Lacrimal/patologia , Neurofibromina 1/genética , Serina-Treonina Quinases TOR/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases , Classe Ib de Fosfatidilinositol 3-Quinase/genética , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Renais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Mutação/genética , Fosfatidilinositol 3-Quinases/genética , Polimorfismo de Nucleotídeo Único/genética , Sarcoma/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Neoplasias da Glândula Tireoide/tratamento farmacológico , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética , Adulto JovemRESUMO
An acidic polysaccharide CS-F2 from Camellia sinensis was examined to characterize its anti-adhesive effects against pathogenic bacteria, most notably Helicobacter pylori, Propionibacterium acnes, and Staphylococcus aureus. CS-F2 showed marked inhibitory activity against the pathogen-mediated hemagglutination with a minimum inhibitory concentration (MIC) between 0.01 and 0.1 mg/mL, which is lower than the previously reported MIC values for Panax ginseng and Artemisia capillaris. The inhibitory effects of CS-F2 on the adhesion of H. pylori to AGS adenocarcinoma gastric epithelial cells, or P. acnes and S. aureus to NIH 3T3 fibroblast cells, were further assessed resulting in MIC values between 0.063 and 0.13 mg/mL. Importantly, CS-F2 showed no inhibitory effects against Lactobacillus acidophilus, Escherichia coli, or Staphylococcus epidermidis. Our results suggest that CS-F2, which is a pectin-type polysaccharide with a molecular weight of approximately 8.0 x 10(4) Da, may exert a selective anti-adhesive effect against certain pathogenic bacteria, while exerting no effects against beneficial and commensal bacteria.