Nucleotide excision repair is a potential therapeutic target in multiple myeloma

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Alkylating agents are crucial in multiple myeloma (MM) therapy.
• DNA repair mechanisms influence patient response to alkylating agents.
• Nucleotide excision repair (NER) removes DNA adducts and crosslinks, potentially affecting MM treatment outcomes.

Purpose of the Study:

• To investigate the role of NER in modulating sensitivity to alkylating agents in MM.
• To identify specific NER pathway components as potential therapeutic targets in MM.

Main Methods:

• Functional assay to evaluate NER activity in MM cell lines and patient samples.
• Next-generation sequencing to correlate ERCC3 gene expression with patient outcomes.
• RNA interference and small-molecule inhibitors to target ERCC3/XPB and assess its impact on MM cell sensitivity to alkylating agents.

Main Results:

• NER efficiency was heterogeneous across MM cell lines and patient samples.
• Higher expression of the NER gene ERCC3 correlated with better outcomes in newly diagnosed MM patients treated with alkylating agents.
• Inhibition of XPB (encoded by ERCC3) via small-molecule inhibitors significantly increased sensitivity and overcame resistance to alkylating agents in MM cells, also inhibiting transcription.

Conclusions:

• NER plays a significant role in determining alkylating agent sensitivity in MM.
• ERCC3, and its encoded protein XPB, represent a promising therapeutic target for enhancing alkylating agent efficacy and overcoming resistance in multiple myeloma.