E3 ubiquitin-protein ligase Mdm2 (HDM2) (HDM2)

HDM2 (Human Double Minute 2), the human homolog of MDM2, is an E3 ubiquitin-protein ligase that acts as the principal negative regulator of the p53 tumor suppressor protein [1]. While HDM2 is typically found in the nucleus and cytoplasm, a specific cell-surface form (csHDM2) has been identified as being overexpressed on the plasma membrane of various cancer cells, including those in sarcomas, leukemias, and certain solid tumors [2, 3]. This cell-surface localization is highly specific to malignant cells, as csHDM2 is largely absent from normal tissues, making it a promising target for selective cancer therapies such as monoclonal antibodies and CAR-T cells [2]. In many cancers, HDM2 is amplified or overexpressed, leading to the inactivation of p53-mediated apoptosis and allowing for tumor progression [1, 4]. Therapeutic strategies targeting HDM2 include small-molecule inhibitors that disrupt the p53-HDM2 interaction to reactivate p53, as well as experimental antibodies designed to exploit the cell-surface form for immune-mediated clearance or targeted drug delivery [3, 4]. The development of agents targeting the cell-surface form aims to improve the therapeutic index by focusing on tumor-specific expression patterns and reducing systemic toxicities [2, 3]. Clinical evaluation of MDM2-targeted therapies often requires patient selection based on MDM2 amplification and the presence of wild-type TP53 [4]. Overall, the cell-surface form of HDM2 represents a novel class of tumor-associated antigens that expands the druggable landscape of the p53 pathway beyond intracellular small molecules [2, 3].

Other names

MDM2HDM2csMDM2csHDM2Human double minute 2 homologp53-binding protein Mdm2Cell-surface MDM2

Small molecule inhibitors bind to the p53-binding pocket of MDM2, preventing the MDM2-p53 interaction and restoring p53-mediated tumor suppression. Monoclonal antibodies targeting the cell-surface form facilitate immune-mediated destruction (e.g., ADCC) or targeted delivery of cytotoxic payloads to cancer cells [2, 3].