Targeting ATP7A-Dependent Copper Metabolic Homeostasis Induces Cuproptosis and Suppresses the Progression of Mutant KRAS-Driven Lung Cancer

Abstract Despite progress in tumor-targeted therapy, oncogenic KRAS remains a major challenge in treating lung adenocarcinoma. In clinical practice, KRASG12C inhibitors have limited response rates and are associated with acquired drug resistance. Cuproptosis is a recently identified form of copper (Cu)-mediated cell death, and previous studies have revealed that Cu metabolism plays an important role in the development of KRAS-driven tumors. In this study, we revealed the therapeutic value of the Cu ionophore elesclomol (ES) for treating KRASG12-mutant–driven lung adenocarcinoma. KRASG12-mutant lung adenocarcinoma cells relied on the Cu exporter ATP7A to maintain Cu homeostasis. ES induced cellular Cu accumulation and cuproptosis by upregulating the expression of the E3 ligase OSTM1, which interacted with the IRGY motif of ATP7A to promote ubiquitination and degradation. KRASG12D transgenic mice and lung cancer organoids derived from the mice were used to validate the therapeutic effects of ES and Cu in vivo and in vitro. These findings indicate that KRASG12-driven lung adenocarcinoma relies on ATP7A-mediated Cu metabolic homeostasis, which can be perturbed with ES as an effective treatment strategy. Significance: The copper ionophore elesclomol is effective for treating KRAS-driven lung cancer by activating the OSTM1-ATP7A regulatory axis to perturb copper metabolism homeostasis.