Exploiting Wnt-induced DNA damage repair vulnerability with PARP inhibitors to overcome chemoresistance in multiple myeloma

Multiple Myeloma (MM) is a plasma cell malignancy characterized by the clonal proliferation of malignant plasma cells in the bone marrow, leading to the excessive production of monoclonal immunoglobulin. This proliferation and the subsequent interaction with the bone microenvironment result in significant end-organ damage, classically represented by the CRAB criteria: C alcium elevation (hypercalcemia), R enal failure, A nemia, and B one lesions (lytic lesions, pain, and fractures). It is a highly aggressive and lethal cancer, notorious for high recurrence rates and a lack of effective targeted therapies. While PARP inhibitors (PARPi) are potent agents, their clinical benefit is narrowly restricted to the small patient subset harboring BRCA mutations. We present a strategy to expand PARPi efficacy in MM. We discovered that the Wnt signaling transcription factor, beta-catenin, controls the expression of the critical Fanconi Anemia DNA repair protein, FANCD2 and cohesion protein CTCF in MM cells. Crucially, inhibiting beta-catenin in initially resistant MM cells (those that are homologous recombination, or HR, proficient) induces a BRCA-like deficiency known as BRCAness and severe replication stress. This combination-beta-catenin inhibition paired with PARPi-shows enhanced DNA damage, striking synergistic lethality in cell models, and powerful anticancer activity in organoid models . This dual-targeting approach offers a novel and effective strategy to overcome resistance in MM.