Therapeutic challenges in HER2-targeted antibody therapies: trastuzumab and its ADC derivatives in breast cancer

Abstract

HER2 overexpression is associated with aggressive and poor patient outcome. HER2 has become a crucial target in cancer treatment, and the discovery of effective HER2-targeted therapies marked a significant milestone in treating HER2-positive cancers. This led to the approval of trastuzumab, the first HER2-targeted monoclonal antibody. Later, trastuzumab was used to develop antibody-drug conjugates (ADCs) for breast cancer, which have shown promising results. ADCs are combined trastuzumab with a cytotoxic drug to improve effectiveness while reducing side effects. Two ADCs, trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), have been approved by the FDA for treating HER2-positive breast cancer. However, drug resistance has become a serious issue, reducing the long-term success of these treatments. This review explores key mechanisms of ADCs resistance including alteration in HER2 expression, antibody and payload-related resistance, altered cell signaling, impaired lysosomal and intracellular activity, and tumor microenvironment. By analyzing recent studies in ADCs resistance, this review provides an insight into ADC resistance mechanisms and potential strategies for improving therapeutic outcomes HER2 positive breast cancer.

Keywords: Antibody-drug conjugates (ADCs); T-DM1; T-DXd; breast cancer; drug resistance.

Figure 1

Schematic representation of the mechanism of action of HER2-targeted antibody - drug conjugate. HER2-targeted ADCs function by specifically binding to HER2 antigens expressed on the surface of cancer cells. Upon binding, the ADCs-antigen complex is internalized and trafficked through the endosomal-lysosomal pathway. Within the lysosome, cleavable linkers are degraded by proteolytic enzymes or acidic conditions, resulting in the release of cytotoxic payloads into the cytoplasm. These payloads can disrupt cellular function, leading to apoptosis or cell death due to bystander effects.

Figure 2

Mechanisms of resistance to HER2-targeted ADCs in breast cancer. Schematic overview of mechanisms of resistance to HER2-Targeted ADCs. Multiple resistance mechanisms limit the efficacy of HER2-targeted ADCs, including reduced HER2 expression, activation of alternative signaling pathways, impaired intracellular trafficking and lysosomal processing, drug efflux, resistance to apoptosis, and modulation by the tumor immune microenvironment.

Figure 3

Potential Strategies to Overcome ADCs resistance in breast cancer. Schematic overview of therapeutic approaches to overcome resistance to HER2-targeted antibody-drug conjugates (ADCs), including trastuzumab, T-DM1, and T-DXd. Strategies are categorized into four major areas: (1) Optimization of ADCs design, including cleavable linkers, site-specific conjugation, payload modification, and enhancement of the bystander effect. (2) Combination therapy such as co-treatment with PI3K/AKT/mTOR pathway inhibitors and DNA damage response modulators to sensitize tumors and overcome oncogenic resistance. (3) Dual-targeting strategies utilizing bispecific ADCs that co-target HER2 and alternative receptors (e.g., EGFR) to improve internalization, overcome antigen escape, or incorporate dual payloads for broader cytotoxic effects. (4) Targeting intracellular processing, including modulation of intracellular trafficking, enhancement of lysosomal degradation, and improved payload release to increase cytotoxic efficacy.