Osimertinib (Osi) is a widely used epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). However, the emergence of resistance is inevitable, partly due to the gradual evolution of adaptive resistant cells during initial treatment. Here, we find that Osi treatment rapidly triggers adaptive resistance in tumor cells. Metabolomics analysis reveals a significant enhancement of oxidative phosphorylation (OXPHOS) in Osi adaptive-resistant cells. Mechanically, Osi treatment induces an elevation of NCOA4, a key protein of ferritinophagy, which maintains the synthesis of iron-sulfur cluster (ISC) proteins of electron transport chain and OXPHOS. Additionally, active ISC protein synthesis in adaptive-resistant cells significantly increases the sensitivity to copper ions. Combining Osi with elesclomol, a copper ion ionophore, significantly increases the efficacy of Osi, with no additional toxicity. Altogether, this study reveals the mechanisms of NCOA4-mediated ferritinophagy in Osi adaptive resistance and introduces a promising new therapy of combining copper ionophores to improve its initial efficacy.
Acrylamides , Aniline Compounds , Carcinoma, Non-Small-Cell Lung , Drug Resistance, Neoplasm , ErbB Receptors , Ferritins , Lung Neoplasms , Protein Kinase Inhibitors , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Drug Resistance, Neoplasm/drug effects , ErbB Receptors/metabolism , ErbB Receptors/antagonists & inhibitors , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Acrylamides/pharmacology , Acrylamides/therapeutic use , Protein Kinase Inhibitors/pharmacology , Cell Line, Tumor , Ferritins/metabolism , Aniline Compounds/pharmacology , Aniline Compounds/therapeutic use , Nuclear Receptor Coactivators/metabolism , Nuclear Receptor Coactivators/genetics , Oxidative Phosphorylation/drug effects , Animals , Mice , Copper/metabolism , Autophagy/drug effects , Mice, Nude , Indoles , Pyrimidines
In ischemia/reperfusion (I/R) injury, both inflammation and apoptosis play a vital role, and the inhibition of excessive inflammation and apoptosis show substantial clinical potential in the treatment of I/R disease. The role of sacubitril/valsartan (SAC/VAL)-a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI)-in inflammation regulation and apoptosis in the context of I/R injury needs to be further explored. In this study, we investigate the short- and long-term effects of SAC/VAL administration in treating adult murine I/R injury both in vivo and in vitro. Our results verified that the application of SAC/VAL could reduce infarct size and suppress apoptosis and the inflammatory response in the acute phase post I/R. Long-term application of SAC/VAL for four weeks significantly improved ventricular function and reversed pathological ventricular remodeling. Mechanistically, SAC/VAL treatment induces the inhibition of the GSK3ß-mediated NF-κB pathway through synergistically blocking angiotensin 1 receptor (AT1R) and activating natriuretic peptide receptor (NPR). In summary, we reported the therapeutic role of SAC/VAL in regulating the GSK3ß/NF-κB signaling pathway to suppress the inflammatory response and apoptosis, thereby reducing cardiac dysfunction and remodeling post I/R.
Myocardial Reperfusion Injury , NF-kappa B , Mice , Animals , NF-kappa B/metabolism , Glycogen Synthase Kinase 3 beta , Myocardial Reperfusion Injury/drug therapy , Neprilysin/therapeutic use , Myocytes, Cardiac/metabolism , Tetrazoles/pharmacology , Tetrazoles/therapeutic use , Valsartan/pharmacology , Inflammation/drug therapy , Receptors, Angiotensin/therapeutic use , Angiotensins/therapeutic use
