Temsirolimus targets chemoresistant uveal melanoma via mammalian target of rapamycin inhibition and enhances chemotherapy

Chemotherapy resistance remains a major challenge in the treatment of uveal melanoma, necessitating the identification of novel therapeutic strategies. In this study, we established chemoresistant uveal melanoma cell lines by exposing parental cells to dacarbazine, cisplatin, or gemcitabine and performed high-throughput drug screening incorporating normal human epidermal melanocytes (NHEMs) as a normal control to assess both efficacy and selectivity. Our screening identified temsirolimus and selumetinib as top candidates, with temsirolimus exhibiting strong tumor-selective cytotoxicity. Further in-vitro studies confirmed that temsirolimus induced apoptosis and suppressed clonogenic potential in chemoresistant uveal melanoma cells while having minimal effects on NHEM. Combination studies demonstrated synergy between temsirolimus and cisplatin or gemcitabine, reinforcing its role as an effective chemosensitizer. In a chemoresistant uveal melanoma xenograft model, temsirolimus significantly inhibited tumor growth without inducing systemic toxicity, as evidenced by stable biochemical markers of organ function. Mechanistically, temsirolimus downregulated mammalian target of rapamycin (mTOR) signaling, as indicated by reduced p-mTOR, p-S6, and p-4EBP1 expression in tumor tissues. These findings demonstrate that temsirolimus selectively targets chemoresistant uveal melanoma cells, enhances chemotherapy efficacy, and suppresses tumor growth via mTOR inhibition, supporting its potential clinical application as a novel therapeutic strategy for chemoresistant uveal melanoma.