Targeting MCM6 Enhances Melphalan Chemosensitivity in Retinoblastoma by Modulating DNA Damage Response

Purpose: This study aimed to investigate the role of minichromosome maintenance complex component 6 (MCM6), a DNA replication licensing factor, in retinoblastoma progression and its impact on melphalan chemosensitivity. Methods: MCM6 expression patterns were analyzed using single-cell RNA sequencing (scRNA-seq) of retinoblastoma and validated in patient tumors, including specimens obtained after failed melphalan therapy. Stable MCM6 knockdown cell lines were established for proliferation and cell-cycle assays, DNA damage analyses, and chemosensitivity testing. In vivo xenograft models were employed to evaluate the therapeutic efficacy of MCM6 knockdown combined with melphalan. Results: The scRNA-seq revealed that MCM6 was highly expressed in retinoblastoma cells and embedded in a proliferation-associated gene network. Elevated expression was also confirmed in human retinoblastoma, particularly in tumors from patients with failed melphalan therapy. MCM6 knockdown suppressed cell proliferation and cell-cycle progression while enhancing melphalan-induced DNA damage, thereby sensitizing retinoblastoma cells to melphalan. In vivo, MCM6 depletion synergized with melphalan to significantly inhibit intraocular tumor growth. Conclusions: MCM6 acts as a critical regulator of retinoblastoma growth and modulates response to melphalan. Targeting MCM6 may offer a therapeutic approach to improve outcomes of chemotherapy in retinoblastoma.