Treatment of dexamethasone and lenalidomide-resistant multiple myeloma via RAD51 degradation using PROTAC and synergistic effects with chemotherapy.

Abstract

Multiple myeloma (MM) is a clonal B-cell malignancy arising from plasma cells in the bone marrow that can lead to various symptoms such as bone pain and fractures, anemia, renal failure and repeated infection. Treatment involves steroids, chemotherapy, targeted therapy and stem cell transplantation. On the other hand, resistance to these treatments often develops, particularly in relapsed/refractory MM, necessitating new strategies. This study examined the degradation of RAD51 recombinase (RAD51) in MM cell lines resistant to existing treatments using proteolysis targeting chimeras (PROTACs). Resistant cell lines were established by exposing human B lymphoblast cell lines, MM.1S and MM.1R, to increasing doses of lenalidomide or pomalidomide. Targeted RAD51 degradation (TRD) 2, a novel PROTAC targeting RAD51, reduced the RAD51 protein levels and cell proliferation. TRD2, combined with chemotherapy drug cisplatin, showed enhanced efficacy in cell proliferation compared to single-agent treatment. In vivo studies confirmed the synergistic effects of TRD2 and cisplatin in inhibiting tumor growth in lenalidomide-resistant MM.1R xenograft models without significant toxicity. MM cells exhibit increased RAD51 expression as they develop resistance to chemotherapy. This study shows that targeting RAD51 with TRD2 enhances the efficacy of DNA-damaging treatments, providing a promising approach for overcoming drug resistance in MM. The inhibition of RAD51 combined with cisplatin therapy can maximize the treatment efficacy of MM patients resistant to dexamethasone and lenalidomide. Nevertheless, further research will be needed to explore the clinical applications of these findings.