Overcoming platinum resistance by the disulfiram metabolite CuET in novel preclinical models of human carcinomas.

Overcoming resistance to standard-of-care chemotherapy represents an unmet need in oncology. To help address this challenge, here we established and characterized a panel of human cisplatin-resistant lung and breast cancer cell lines and patient-derived organoids from high-grade serous ovarian carcinomas (HGSOC), and show that platinum resistance can be overcome by treatment with diethyldithiocarbamate-copper (CuET), a metabolite of the alcohol-aversion drug disulfiram. All platinum-resistant models remained sensitive to CuET, consistent with distinct cytotoxicity mechanisms: proteotoxic stress for CuET and DNA damage for cisplatin, respectively. Platinum adduct and DNA damage response analyses suggested diverse mechanisms of cisplatin resistance among our models. Considering potential CuET-based therapies, our gene knock-down and functional assays in preclinical models, complemented with immunohistochemical analysis of tissue samples from cohorts of triple-negative breast cancer and HGSOC patients indicate that levels of metallothioneins, rather than NPL4 (the molecular target of CuET) warrant further evaluation as candidate biomarkers of CuET sensitivity. This dataset provides a resource of platinum-resistant models of common carcinomas, identifies CuET as a compound overcoming such resistance and provides leads for predictive biomarker discovery, with potential clinical implications in oncology.