Transcriptomic and proteomic signatures predict in vitro response to mitotane in adrenocortical carcinoma

OBJECTIVE: Mitotane is e first-line medical treatment for adrenocortical carcinoma (ACC). Mitotane has substantial dr awbacks, including severe toxicity and contralateral gland destruction, whilst effective in only 25-30% of ACCs. To improve patient selection for mitotane therapy, this study aimed to identify tissue biomarkers associated with in vitro mitotane response. DESIGN: Retrospective cohort study. METHODS: We performed transcriptomic and proteomic analyses on fresh-frozen human ACC tissues classified as responders (n=13), partial responders (n=10), or non-responders (n=7) based on in vitro mitotane-induced inhibition of cell proliferation. RESULTS: Responders showed distinct transcriptomic and proteomic signatures compared with partial and non-responders, whereas fewer differences were found between the latter groups. Integrating transcriptomic and clinicopathological data indicated that responders frequently had cortisol-producing ACC with metastases or nodal involvement. Furthermore, their transcriptomes aligned with aggressive, proliferative ACC subtypes described previously. Differential expression analysis identified 718 genes and 60 proteins that distinguished responders from non-responders. Pathway and network analyses revealed upregulation of cell cycle and collagen related genes and downregulation of mitochondria related genes and proteins in responders. CONCLUSIONS: In summary, transcriptomic and proteomic profiling offers promise to predict mitotane response in ACC. Our findings suggest that responders exhibit features of aggressive ACC, with distinct molecular characteristics that could serve as biomarkers for treatment selection.