Targeting matrix metalloproteinase-14 disrupts DNA repair and reduces viability in adrenocortical carcinoma.

Background: Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine cancer with limited treatment options and poor prognosis. Identifying novel therapeutic targets requires understanding the molecular drivers of ACC progression and establishing translational models for preclinical validation. Results: Matrix metalloproteinase-14 (MMP-14) is the most highly expressed MMP in ACC, and high MMP-14 expression is associated with worse overall and disease-free survival. We demonstrate that MMP-14 is essential for ACC cell survival and serves an unexpected role in maintaining genome stability. Genetic silencing or pharmacologic inhibition of MMP-14 significantly reduced viability in both NCI-H295R cells and patient-derived tumor organoids (PTOs). MMP-14 knockdown induced CHK1 activation and S-phase checkpoint arrest. Mechanistically, MMP-14 translocates to the nucleus and binds to chromatin following DNA damage induced by ionizing radiation or cisplatin. Loss of MMP-14 resulted in accumulation of DNA double-strand breaks, as evidenced by increased γH2AX foci, and impaired non-homologous end joining (NHEJ)-mediated repair. Conclusions: These findings reveal a novel nuclear function for MMP-14 in DNA repair and identify MMP-14 as a promising therapeutic target in ACC. Targeting MMP-14 may sensitize ACC tumors to DNA-damaging chemotherapy by impairing the repair of therapy-induced lesions.