ArticleGenome biology2026
Proteogenomic decoding of chemotherapy resistance in patients with triple-negative breast cancer.
Article in Genome biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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21 authors.
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Abstract
backgroundThe clinical utility of integrated proteogenomic biomarkers for predicting chemotherapy response in triple-negative breast cancer remains underexplored. We prospectively analyzed paired baseline and post-treatment tumor samples from 50 patients with stage II-III TNBC treated with anthracycline- and taxane-based neoadjuvant chemotherapy, integrating whole-exome sequencing, RNA sequencing, global proteomics, and phosphoproteomics.
resultsNon-negative matrix factorization clustering identifies five proteogenomic subtypes. The immune-enriched subtype demonstrates the highest pathologic complete response rate (55.6%), whereas no pathologic complete response was observed in the xenobiotic metabolism or epithelial-mesenchymal transition subtypes. Immune-related pathways are enriched in tumors with pathologic complete response, while epithelial-mesenchymal transition pathways are enriched in non-pathologic complete response tumors. The estrogen response pathway is selectively enriched in non-pathologic complete response tumors at the proteomic level and inversely correlated with immune activation. Post-translational modification and in vitro analyses suggest estrogen-linked GRK2 activation contributes to chemotherapy resistance. ITGB8 copy number loss is associated with higher pathologic complete response rates and immune activation, while non-pathologic complete response tumors of the immunomodulatory subtype show increased expression of AKR1C2 and ABCA13. Comparison of baseline and post-treatment tumors reveals AURKB pathway activation in residual disease, with Aurora B kinase inhibition synergizing with paclitaxel. A predictive model incorporating these biomarkers outperforms RNA-based models in predicting response.
conclusionIntegrative proteogenomic profiling enables robust prediction of chemotherapy resistance in triple-negative breast cancer and identifies actionable biomarkers providing a framework for advancing personalized therapeutic strategies.
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