Deruxtecan-based antibody–drug-conjugates induce senescence in HER2-positive breast cancer

Breast cancer (BrCa) represents one of the most common malignancies and the leading cause of cancer-related deaths in women worldwide. Despite the advances in therapeutic treatments, de novo and/or acquired resistance still represents a major clinical challenge. Recently, a new class of therapeutic agents has been approved for the treatment of advanced/metastatic BrCa: antibody–drug conjugates (ADCs). Trastuzumab-deruxtecan (T-DXd) has recently become the prevalent treatment in different clinical settings because of its improved efficacy. Here, we identified two mechanisms of resistance: i. reduction of the payload target (Topoisomerase I) and ii. induction of sustained senescence. This phenotype correlates with increased production of reactive oxygen species (ROS), metabolic rewiring and activation of the p53/p21 axis, and is associated to the senescence-associated secretory phenotype (SASP). Furthermore, dissection of the relative contribution of the antibody (Trastuzumab) vs the payload (DXd) component of the ADC to the action of T-DXd showed that DXd alone is sufficient to promote senescence and its downstream effects. We further corroborated these conclusions exploiting another DXd-based ADC (Datopotamab-DXd) and found that DXd-based drugs promote Topoisomerase I downregulation and senescence. Altogether, these findings provide the rationale for the treatment of breast cancer patients resistant to DXd-based ADCs with senolytic or senomorphic agents.