Targeting ATP7A-dependent copper metabolic homeostasis as a therapeutic strategy for KRASG12-driven LUAD

Despite progress in tumor-targeted therapy, oncogenic KRAS remains a major challenge in LUAD treatment. In clinical practice, KRASG12C inhibitors are facing trouble of limited response rate and acquired drug resistance. Cuproptosis has emerged as a research focus in cancer biology, and previous studies revealed that Cu metabolism plays an important role in the development of KRAS-driven tumors. Here, we investigated the mechanism of the Cu ionophore elesclomol in the targeted killing of KRASG12-mutated LUAD. The expression of the Cu transporter ATP7A is strongly correlated with KRAS signaling in pan-cancer, including LUAD. In KRASG12-mutated LUAD, ATP7A is highly expressed to maintain Cu homeostasis. Elesclomol can downregulate ATP7A by upregulating OSTM1, which can interact with ATP7A and mediate the ubiquitination and degradation of ATP7A, resulting in cellular Cu accumulation, thereby mediating cuproptosis. Taken together, these results indicate that targeting ATP7A-dependent homeostasis of Cu metabolism could be a therapeutic strategy for KRASG12-driven LUAD.