Gene expression changes in 786-O cells in response to Everolimus, SGI-1027, or their combination.

Renal cell carcinoma (RCC) is one of the most common malignant tumors of urinary system. The Food and Drug Administration (FDA) has approved everolimus for the treatment of advanced RCC, but r everolimus resistance limits its application in clinic. We here reported the DNA methyltransferase 1 (DNMT1) inhibitor SGI-1027 as an inducer of methuosis, a type of cell death form independent of apoptosis. Additionally, SGI-1027 and everolimus worked in concert to suppress the proliferation, migration, and invasion of renal cancer cells while also inducing apoptosis and GSDME-dependent pyroptosis. In vitro transplanted tumor mice models, everolimus combined with SGI-1027 played a significant inhibitory effect on the growth of renal cancer tumors with good tolerance. The objective of this study is to explore the mechanism of the synergistic effect of everolimus and SGI-1027. We demonstrated through analysis of transcriptome high-throughput sequencing data that lysosomes were strongly linked with the synergistic effect of everolimus and SGI-1027 at the transcriptional level, which provides a new strategy for everolimus resistance and the treatment of advanced RCC.