Repurposing Alkylating Agents in Melanoma via ERCC8 Silencing: A Novel Therapeutic Strategy

TL;DR

This study shows that reducing a DNA repair protein called CSA makes melanoma cells more vulnerable to chemotherapy, potentially improving treatment for resistant cases.

Contribution

The study identifies CSA/ERCC8 as a novel target to enhance chemotherapy effectiveness in melanoma by overcoming chemoresistance.

Findings

CSA/ERCC8 is overexpressed in melanoma cells and contributes to chemoresistance.

ERCC8 silencing increases chemotherapy sensitivity while sparing normal cells.

Targeting CSA enhances the efficacy and selectivity of alkylating agents in melanoma.

Abstract

Melanoma is an aggressive skin cancer that can become resistant to modern immunotherapies and targeted treatments. When this occurs, chemotherapy drugs such as temozolomide and dacarbazine are still used, but their benefit is limited because melanoma cells can repair the DNA damage caused by these drugs, and high doses may cause significant side effects. In this study, we investigated a protein called CSA, which is involved in DNA repair and helps cells survive under stress. We found that melanoma cells depend strongly on CSA to maintain their growth and resist chemotherapy. By reducing CSA levels using antisense oligonucleotides, we weakened melanoma cells, reduced their ability to grow and migrate, and increased cell death. Importantly, CSA inhibition made melanoma cells much more sensitive to low doses of chemotherapy, while normal cells were largely spared. These findings suggest that targeting CSA could improve the effectiveness and selectivity of existing chemotherapy, particularly in resistant or metastatic melanoma, and may represent a new strategy to enhance treatment options for patients with advanced disease.

Background/Objectives: Melanoma is the deadliest form of skin cancer. Resistance to alkylating agents such as Temozolomide (TMZ) and Dacarbazine (DTIC) limits their clinical benefit, as these drugs remain palliative options when immunotherapies and targeted treatments fail. CSA/ERCC8 is a key component of transcription-coupled nucleotide excision repair (TC-NER), a pathway responsible for removing UV-induced DNA lesions. In principle, loss of a DNA repair factor would be expected to increase carcinogenesis. However, although CSA loss-of-function causes Cockayne Syndrome (CS), affected patients do not exhibit increased skin cancer incidence, suggesting that CSA impairment promotes apoptosis rather than tumor development. This paradox raises the possibility that CSA inhibition may selectively target melanoma cell survival pathways. Methods: The expression of CSA/ERCC8 was analyzed by qRT-PCR and Western blot. ERCC8 was silenced using antisense oligonucleotides. Cell viability, apoptosis, cell cycle progression, drug sensitivity, and DNA damage were assessed by functional assays, including IC50 determination and Bliss analysis for drug interactions. Results: We identified CSA/ERCC8 as a driver of melanoma chemoresistance. CSA was markedly overexpressed in primary and metastatic melanoma cells. ERCC8 silencing reduced proliferation, induced apoptosis, and significantly enhanced sensitivity to low doses of TMZ and DTIC while sparing normal cells. Conclusions: CSA represents a promising therapeutic target to overcome chemoresistance in melanoma. Its inhibition enhances the efficacy and selectivity of alkylating agents, supporting its potential as a salvage strategy for refractory disease and warranting further preclinical and clinical investigation.

Figures