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Mol Cancer Res ; 19(4): 726-738, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33563765

RESUMO

Gefitinib is suitable for the treatment of locally advanced or metastatic non-small cell lung cancer. However, the development of acquired resistance limits its long-term efficacy in regardless of significant clinical benefit to patients. Therefore, to elucidate the mechanism of gefitinib resistance in addition to target gene mutation may greatly increase its clinical efficacy. It was found first that N 6-methyladenosine RNA demethylase FTO was significantly enriched in serum exosomes of gefitinib-resistant (GR) patients compared with that of gefitinib-sensitive (GS) patients through exosomal RNA sequencing. Meanwhile, the average m6A proportion in GR patients was significantly lower when compared with that in GS patients. Besides, GR cell-derived exosome internalization attenuated the total m6A abundance and gefitinib sensitivity of PC9 cells. Not only FTO knockdown enhanced the gefitinib sensitivity of GR cells but also FTO reduction in donor exosomes alleviated the acquired resistance of recipient PC9 cells. GR cell-derived exosomal-FTO promoted ABCC10 of recipient cells in a m6A-dependent manner. FTO/YTHDF2/ABCC10 axis played a role in intercellular transmission of GR cell-derived exosome-mediated gefitinib resistance both in vitro and in vivo. In general, this research showed that m6A modification was involved in the decrease of gefitinib sensitivity. GR cell-derived exosomes could decrease gefitinib sensitivity of recipient cells in exosomal delivery of FTO-dependent manner. FTO/YTHDF2/ABCC10 axis played a role in intercellular transmission of GR cell-derived exosome-mediated gefitinib resistance. IMPLICATIONS: Our results elucidated another potential molecular mechanism of gefitinib resistance in non-small cell lung cancer besides secondary EGFR mutations.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Exossomos/metabolismo , Gefitinibe/uso terapêutico , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Linhagem Celular Tumoral , Gefitinibe/farmacologia , Humanos , Transdução de Sinais
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