A Cuproptosis Nanoparticle Reverses Lung Adenocarcinoma Drug Resistance

ABSTRACT Residual tumors that received targeted therapy often evolve into drug resistance, with an increasing risk of recurrence and metastasis. By analyzing patient data, it is found that KRAS ‐mutated lung adenocarcinoma (LUAD) exhibits a worse survival rate than wild‐type LUAD. Although the clinical drug AMG‐510 has been approved to treat KRAS(G12C) ‐mutated LUAD, its effectiveness is still limited by drug resistance. Cuproptosis, a newly identified mode of cellular death, shows promise in cancer treatment and in reversing drug resistance. By comparing cell lines with different sensitivities to AMG‐510, we discovered that ATP7B , a key regulator of cuproptosis, was up‐regulated in AMG‐510‐resistant cell lines to decrease their sensitivity to cuproptosis. Therefore, a targeted sensitization strategy focused on cuproptosis was proposed using a single nanoparticle based on bovine serum albumin encapsulating copper ions (termed CuNPs). Both in vitro and in vivo results demonstrated that these nanoparticles released copper ions in an acidic environment, and the following CuNP‐triggered cuproptosis could effectively down‐regulated ATP7B , which successfully overcame AMG‐510 resistance with a synergistic antitumor effect. Collectively, targeting cuproptosis in KRAS‐mutated lung adenocarcinoma emerges as a compelling strategy to address drug resistance.