2024 Asia Conference on Lung Cancer (ACLC) - Poster & ePosters-PP02.34

PP02.34 - Zeyi Liu

Pdf Summary

This study explores a novel therapeutic approach for treating lung adenocarcinoma (LUAD) driven by the KRASG12 mutation, which typically leads to poor patient outcomes. Researchers focused on targeting copper metabolism homeostasis, specifically the ATP7A-dependent pathway, as a potential treatment strategy. Elesclomol (ES), a copper ionophore, was identified as a promising agent due to its ability to induce endoplasmic reticulum stress and upregulate the expression of E3 ubiquitin ligase OSTM1. This upregulation triggers the ubiquitination and degradation of ATP7A, disrupting intracellular copper homeostasis and leading to cell death via cuproptosis. <br /><br />In vitro and in vivo experiments demonstrated that KRASG12 mutant LUAD cells heavily rely on ATP7A for copper export and maintaining copper balance. Treatment with ES exacerbates copper overload in these cells by promoting ATP7A degradation, offering a new mechanism of action against tumor growth. The in vivo results, using transgenic mice with KRASG12D mutations, showed that ESCu treatment significantly reduced lung adenocarcinoma lesions compared to controls.<br /><br />This study highlights a potential therapeutic strategy that leverages the vulnerability of KRASG12 mutant LUAD cells in maintaining copper homeostasis, offering a new approach that might complement existing cancer therapies. By targeting the copper export mechanism disrupted by ES, new therapeutic options could be developed for patients with KRAS mutations, contributing to advancements in understanding the role of trace metal ion metabolism in cancer cells.

Keywords

lung adenocarcinoma

KRASG12 mutation

copper metabolism

ATP7A pathway

Elesclomol

endoplasmic reticulum stress

OSTM1

cuproptosis

copper homeostasis

cancer therapy