Lung adenocarcinoma (LADC), the most common type of lung cancer, is still one of the most aggressive and rapidly fatal tumor types, even though achievements in new therapeutic approaches have been developed. Elaiophylin as a C2 symmetrically glycosylated 16 macrolides has been reported to be a late-stage autophagy inhibitor with a potent anti-tumor effect on various cancers. This study investigated the anti-tumor effect of elaiophylin on human LADC for the first time in in vitro and in vivo models. The in vitro study in LADC A549 cells showed that elaiophylin significantly inhibited cell viability and induced cell apoptosis through the suppression of mitophagy and induction of cellular and mitochondrial oxidative stress. Proteomic analysis and molecular docking assay implicated that SIRT1 was likely the direct target of elaiophylin in A549 cells. Further mechanistic study verified that elaiophylin reduced Nrf2 deacetylation, expression, and transcriptional activity as well as cytoplasm translocation by downregulating SIRT1 expression and deacetylase activity. Additionally, SIRT1/Nrf2 activation could attenuate elaiophylin-induced mitophagy inhibition and oxidative stress. The in vivo study in the A549-xenograft mice model showed that the anti-tumor effect of elaiophylin was accompanied by the decreased expressions of SIRT1, Nrf2, Parkin, and PINK1. Thus, the present study reports that elaiophylin has potent anti-tumor properties in LADC, which effect is likely mediated through suppressing the SIRT1/Nrf2 signaling. In conclusion, elaiophylin may be a novel drug candidate for LADC and SIRT1 may be a new therapeutic target for such devastating malignancy.

Lung adenocarcinoma (LADC) is the most prevalent lung cancer sub-type, and targeted therapy developed in recent years has made progress in its treatment. Erdafitinib, a potent and selective pan-FGFR tyrosine kinase inhibitor, has been confirmed to be effective for the treatment of LADC; however, the molecular mechanism responsible for this effect is unclear. The in vitro study showed that erdafitinib exhibited an outstanding anti-cancer activity in human LADC cell line A549 by inducing S-phase cell-cycle arrest and cell apoptosis. The mechanistic study based on the transcriptomic data revealed that erdafitinib exerted its anti-cancer effect by affecting the cell cycle-related pathway, and CDK2 was the regulatory target of this drug. In addition, CDK2 overexpression significantly attenuated the anti-cancer effect of erdafitinib by affecting the transcriptional activity and expression of E2F1, as well as the expression of CDK1. The in vivo study showed that erdafitinib presented an obvious anti-cancer effect in the A549 xenograft mice model, which was accompanied by the reduced expression of CDK2. Thus, this study demonstrates the anti-cancer effect of erdafitinib against LADC for the first time based on in vitro and in vivo models, whose activity is achieved by targeting CDK2 and regulating downstream E2F1-CDK1 signaling. This study may be helpful for expanding the clinical application of erdafitinib in treating LADC.