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.

中文翻译：

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FTO 的外泌体递送以 m6A 依赖性方式通过 ABCC10 调节赋予受体细胞吉非替尼抗性

吉非替尼适用于局部晚期或转移性非小细胞肺癌的治疗。然而，获得性耐药的发展限制了其长期疗效，无论对患者有显着的临床益处。因此，阐明除靶基因突变外的吉非替尼耐药机制可能会大大提高其临床疗效。通过外泌体RNA测序首次发现，与吉非替尼敏感（GS）患者相比，吉非替尼耐药（GR）患者的血清外泌体中N 6-甲基腺苷RNA去甲基化酶FTO显着富集。同时，与 GS 患者相比，GR 患者的平均 m6A 比例显着降低。此外，GR 细胞衍生的外泌体内化减弱了 PC9 细胞的总 m6A 丰度和吉非替尼敏感性。不仅 FTO 敲低增强了 GR 细胞对吉非替尼的敏感性，而且供体外泌体中 FTO 的减少也减轻了受体 PC9 细胞的获得性耐药性。GR 细胞衍生的外泌体-FTO 以 m6A 依赖性方式促进受体细胞的 ABCC10。FTO/YTHDF2/ABCC10 轴在体外和体内 GR 细胞衍生的外泌体介导的吉非替尼耐药的细胞间传递中发挥作用。总的来说，这项研究表明 m6A 修饰参与了吉非替尼敏感性的降低。GR 细胞衍生的外泌体可降低受体细胞对 FTO 依赖的外泌体递送的吉非替尼敏感性。FTO/YTHDF2/ABCC10 轴在 GR 细胞衍生的外泌体介导的吉非替尼耐药的细胞间传递中发挥作用。影响：