Abstract：
The mTOR inhibitor everolimus has been approved as a sequential or second-line therapy for renal cell carcinoma (RCC). However, the development of drug resistance limits its clinical applications. This study aims to address the challenge of everolimus resistance and provide new insights into the treatment of advanced RCC. Here, the cytotoxicity of the DNA methyltransferase 1 (DNMT1) inhibitor SGI-1027 in inducing cell vacuolation and methuosis is discovered and demonstrated for the first time. Additionally, SGI-1027 exerts synergistic effects with everolimus, as their combination suppresses the growth, migration, and invasion of renal cancer cells. Mechanistically, apoptosis and GSDME-dependent pyroptosis triggered by lysosomal membrane permeability (LMP) are observed. The upregulation of GSDME expression and increased lysosomal activity in renal cancer cells provide a therapeutic window for the combination of these two drugs to treat renal cancer. The combination treatment exhibits effective anti-tumor activity and is well tolerated in a subcutaneous tumor model. Overall, this study validates and reveals the specific cytotoxicity property of SGI-1027 and its potent synergistic effect with everolimus, offering new insights into advanced RCC therapy and everolimus-resistance overcoming.
摘要：
mTOR抑制剂依维莫司已被批准作为肾细胞癌（RCC）的序贯或二线疗法。然而,耐药性的发展限制了其临床应用。本研究旨在解决依维莫司耐药性的挑战，并为晚期RCC的治疗提供新的见解。这里,首次发现并证明了DNA甲基转移酶1（DNMT1）抑制剂SGI-1027在诱导细胞空泡化和甲醇化方面的细胞毒性。此外,SGI-1027与依维莫司发挥协同作用，因为它们的结合抑制了生长，迁移,和肾癌细胞的侵袭。机械上,观察到由溶酶体膜通透性（LMP）触发的凋亡和GSDME依赖性焦亡。肾癌细胞中GSDME表达的上调和溶酶体活性的增加为这两种药物的组合治疗肾癌提供了治疗窗口。联合治疗显示出有效的抗肿瘤活性,并且在皮下肿瘤模型中具有良好的耐受性。总的来说,这项研究验证并揭示了SGI-1027的特定细胞毒性特性及其与依维莫司的有效协同作用，为晚期肾癌治疗和依维莫司耐药性克服提供新的见解。
