Repurposing Alkylating Agents in Melanoma via CSA Silencing: A Novel Therapeutic Strategy

Melanoma is the deadliest form of skin cancer, with resistance to alkylating agents such as Temozolomide (TMZ) and Dacarbazine (DTIC) further limiting the efficacy of these drugs, which remain palliative options when modern immunotherapies and targeted therapies fail. Here, we identify the Cockayne Syndrome group A (CSA) protein—a key component of Transcription-Coupled Nucleotide Excision Repair (TC-NER)—as a novel driver of melanoma chemo-resistance. CSA is markedly over-expressed in both primary and metastatic melanoma cells. Silencing CSA using Antisense Oligonucleotides (ASOs) robustly reduces melanoma cell proliferation, induces apoptosis, and—critically—sensitizes cells to low doses of TMZ and DTIC, while sparing normal cells. Notably, although CSA loss-of-function underlies Cockayne Syndrome (CS), a disorder characterized by defective repair of UV-induced DNA damage, these patients do not exhibit an increased incidence of skin cancer. This paradox highlights a unique biological context in which impaired CSA function promotes cellular apoptosis rather than carcinogenesis, suggesting that CSA inhibition could selectively cripple melanoma cells. These findings establish CSA as a promising therapeutic target to overcome chemo-resistance in melanoma. Combining CSA inhibition with alkylating agents offers a potential salvage strategy in patients with refractory disease and warrants further preclinical and clinical investigation.