Targeting transcription-replication conflicts using G-quadruplexes stabilizers in multiple myeloma.

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Replication stress and transcription-replication conflicts (TRCs) drive genomic instability and drug resistance in multiple myeloma (MM).
• Malignant plasma cells (PCs) in MM experience high transcriptional stress due to immunoglobulin production.
• A previously identified TRC score signature indicates poor prognosis in MM patients.

Purpose of the Study:

• To investigate the therapeutic potential of increasing TRCs to selectively target MM cells.
• To evaluate pyridostatin (PDS), a G-quadruplex (G4) stabilizer, as a TRC-enhancing therapy for MM.
• To assess PDS's efficacy alone and in combination with existing MM treatments.

Main Methods:

• Treatment of MM cell lines and primary MM cells with PDS.
• Assessment of PDS-induced DNA damage, cell cycle arrest, and apoptosis.
• Evaluation of PDS's synergistic effects with melphalan, histone deacetylase (HDAC), and bromodomain (BRD) inhibitors.

Main Results:

• PDS demonstrated significant toxicity towards MM cells, inducing DNA damage, cell cycle arrest, and apoptosis.
• Primary MM cells were more sensitive to PDS than normal bone marrow cells.
• PDS enhanced the efficacy of melphalan, HDAC inhibitors, and BRD inhibitors in MM treatment.

Conclusions:

• G4 stabilizers like PDS can specifically target MM cells by increasing TRCs, offering a novel therapeutic strategy.
• PDS shows promise as a standalone treatment and as an adjuvant therapy to improve outcomes for MM patients.
• Targeting TRCs represents a potential Achilles' heel for MM, particularly in cells with high transcriptional and replication stress.