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William J. Gradishar, MD, FACP, FASCO


Copper-Related Genes and Response to Trastuzumab in HER2-Positive Disease

By: Celeste L. Dixon
Posted: Thursday, April 4, 2024

In HER2-positive breast cancer, genes related to a type of programmed cell death called cuproptosis may help to predict response to therapy with the monoclonal antibody trastuzumab in HER2-positive breast cancer. Sun et al, of Xuzhou Medical College Affiliated Huaian Hospital, Jiangsu, China, and colleagues described their database-centered work relating to these genes in Scientific Reports. Cuproptosis involves mitochondrial lipoylation and destabilization of iron-sulfur proteins triggered by copper.

A total of 14 cuproptosis-related genes are known, according to the investigators. They constructed a signature of four of them—DLAT, SLC31A2, SLC25A3, and ATOX1—as a prognostic prediction model for the degree of resistance to trastuzumab a patient’s cancer may have. Those patients with a high-risk score, as indicated by those cuproptosis-related genes, tended to have shorter overall survival.

DLAT was an independent prognostic factor related to resistance to HER2-targeted therapy, the investigators additionally found. The downregulation of DLAT seemed to correlate with better survival in patients with HER2-positive breast cancer (P = .022). Also, the “negative correlation between TIDE (tumor immune dysfunction and exclusion) and DLAT expression (P < .001) [means] that high DLAT expression is an indicator of sensitivity to immunotherapy,” they wrote. “The TIDE algorithm is a recently developed tool for determining the efficacy of tumor immune checkpoint therapy.”

The authors employed The Cancer Genome Atlas as well as analysis of the Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology enrichment of differential expression genes in the Gene Expression Omnibus data set. The team focused on cuproptosis, which occurs via direct binding of copper to lipoylated components of the tricarboxylic acid cycle, because “this results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss.” In turn, this “lead[s] to proteotoxic stress and ultimately cell death.

Disclosure: The study authors reported no conflicts of interest.

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