MDM2 in multiple myeloma: an emerging candidate from functional screenings driving proteasome inhibitors resistance

Multiple Myeloma (MM) is a neoplastic systemic malignant plasma-cell disorder, the second most common hematologic malignancy after lymphoma. The asymptomatic premalignant proliferation of monoclonal plasma cells, derived from post–germinal-center B cells, and aberrant production of monoclonal antibody characterizes the disease that can ultimately lead to end-organ damage and death. The lack of a full comprehension of its etiopathogenesis, together with the heterogeneity of its genetics, are serious obstacles to the full eradication of MM. The backbone of MM treatment is represented by the Proteasome Inhibitors used in combined therapeutic regimens with immunomodulatory agents, monoclonal antibodies and histone deacetylase inhibitors for both newly diagnosed patients and relapsed/refractory ones. Despite the advancements in therapeutic approaches, the acquisition of anti-cancer drug resistance still seriously affects clinical outcomes. Screening-based approach has emerged within the most reliable tools to investigate on cancer dependencies involved in drug resistance. In this study, we integrated two different functional approaches to reveal synthetic lethal interactions under Carfilzomib selective pressure. From a genome-wide CRISPR activation screening based on the Synergistic Activation Mediator (SAM) system and a pooled human sgRNAs library, MDM2 emerged as a potential gene candidate modulating CFZ resistance. In addition, NVP-CGM097, an MDM2 selective inhibitor, showed to synergize with Carfilzomib treatment in a pharmacological screening. Taken together, our data allowed us to hypothesize that: 1) MDM2 transactivation enhances MM cells recovery after cytotoxic CFZ treatment; 2) MDM2 transactivation confers proliferative advantage in cell competition assays under CFZ treatment; 3) Pharmacological inhibition of MDM2 by NVP-CGM097 exerts a synergistic effect with CFZ treatment. All considered, our preliminary results suggest an MDM2 role in driving CFZ resistance. Given the central biological role played by this gene, and the existence of pharmacological inhibitors currently in clinical trials, further studies for a full elucidation of the mechanisms involved in Multiple Myeloma will be fundamental.