Transcriptomic profiling of [177Lu]Lu-PSMA-I&T and [225Ac]Ac-PSMA-I&T treated prostate cancer cells: insights into dynamic responses

ABSTRACT Background Metastatic prostate cancer remains a major clinical challenge, as current treatments often fail to induce durable responses. Targeted radionuclide therapy (TRT) is a promising option that uses either α- or β - -emitting radionuclides to deliver cytotoxic radiation to prostate-specific membrane antigen-expressing cells. However, clinical outcomes remain insufficient and variable. Tailoring radionuclide choice to tumor-specific characteristics may enhance therapy efficacy, but the biological processes triggered by TRT remain poorly understood. Methods We used bulk RNA sequencing to investigate genome-wide transcriptomic changes in prostate cancer cells treated with an equitoxic dose of [ 225 Ac]Ac-PSMA-I&T or [ 177 Lu]Lu-PSMA-I&T at early (24h) and later (72h) time points. Differential gene expression and pathway enrichment analyses, using distinct interaction models, were performed to secure an unbiased overview of treatment- and time-dependent early gene expression changes. Results Our analysis revealed distinct pathway modulations, such as those related to cell migration and DNA damage response processes, including a more pronounced early transcriptomic response to [ 225 Ac]Ac-PSMA-I&T compared to [ 177 Lu]Lu-PSMA-I&T, followed by a progressive return toward the transcriptomic profile of untreated control cells over time. While bulk-RNA sequencing revealed dynamic transcriptional trends, it lacked sufficient resolution to distinguish heterogeneous TRT-induced responses within the treated cell population. Conclusions These findings demonstrate the potential of transcriptomic analysis to elucidate TRT-induced biological processes and highlight the need for advanced approaches, such as single-cell omics, to resolve heterogeneous cellular responses and guide more effective therapeutic strategies.