Targeting Transcription-Replication Conflicts using G-quadruplexes stabilizers in Multiple Myeloma

• High-risk MM patients overexpressed genes involved in TRC resolution suggesting that they could benefit from a TRC-enhancing therapy.

• Increasing TRCs with G4 stabilizers increases the efficacy of current MM treatments such as melphalan and HDAC or BRD inhibitors.

Replication stress exerts an important role in fueling genomic instability characterizing Multiple Myeloma (MM) evolution, and is a leading cause of drug resistance. Normal and malignant plasma cells (PCs) are associated with a high transcriptional stress due to the huge production of immunoglobulins. Transcription-Replication Conflicts (TRCs) arising from collisions between replication and transcription machineries can promote tumor progression and represent an Achilles’ heel to cancer cells. We reported a gene signature related to TRCs management (TRC score) overexpressed in malignant versus normal PCs. High TRC score identified MM patients with a poor prognosis who could benefit from a TRC-enhancing therapy, in independent cohorts of MM patients treated with high dose melphalan chemotherapy or anti-CD38 immunotherapy. Here, we investigated the therapeutic interest of increasing TRCs to target specifically malignant PCs using the G-quadruplex (G4) stabilizer Pyridostatin (PDS). PDS exerted significant toxicity in MM cell lines and primary MM cells, induced DNA damage, cell cycle arrest and apoptosis. Importantly, primary myeloma cells are significantly more sensitive to PDS treatment than normal bone marrow cells. Moreover, PDS improved the efficacy of MM treatments such as melphalan and HDAC or BRD inhibitors. Thus, our study shows that G4 stabilizers could be used to specifically target MM cells that exhibit concomitant replication stress and a high level of transcription, through the increase of TRCs. These molecules could be used to increase the efficacy of other treatments including melphalan, HDAC inhibitors, and BRD inhibitors.