Antibody-drug conjugates (ADCs) are a promising class of targeted cancer therapies that use monoclonal antibodies to selectively deliver potent cytotoxic agents to cancer cells. Despite the success of some ADCs in preclinical and clinical studies, the development of resistance to these drugs remains a major challenge in cancer treatment. Resistance to ADCs can occur through several mechanisms, including alterations in the expression or function of the target antigen, changes in the intracellular trafficking and processing of the ADC, and activation of survival pathways.
Alterations in the expression or function of the target antigen:
ADCs target specific antigens expressed on the surface of cancer cells. Resistance to ADCs can arise if there is a decrease in the expression or function of the target antigen. This can occur through various mechanisms, such as the loss of the antigen due to genetic or epigenetic changes, the shedding of the antigen into the extracellular space, or the down-regulation of the surface expression of the antigen. For example, resistance to trastuzumab emtansine (T-DM1), an ADC that targets HER2, can occur due to the loss of HER2 expression or the emergence of HER2-negative tumor cells.
Changes in the intracellular trafficking and processing of the ADC:
After binding to the target antigen on the surface of cancer cells, ADCs are internalized and transported to lysosomes, where the cytotoxic agent is released and causes cell death. Resistance to ADCs can arise if there are changes in the intracellular trafficking and processing of the ADC, such as altered lysosomal pH or lysosomal enzyme activity, which can affect the release of the cytotoxic agent. For example, resistance to brentuximab vedotin (BV), an ADC that targets CD30, can occur due to mutations in lysosomal enzymes that degrade the ADC.
Activation of survival pathways:
Cancer cells can activate survival pathways that enable them to evade the cytotoxic effects of ADCs. For example, the activation of the PI3K/AKT pathway can promote cell survival and resistance to ADCs that target the HER2 receptor. Similarly, the activation of the MAPK pathway can promote cell survival and resistance to ADCs that target the EGFR receptor.
Efflux of the cytotoxic agent:
Efflux pumps are membrane transporters that can pump drugs out of cells, thereby reducing their intracellular concentration and efficacy. Resistance to ADCs can occur if cancer cells upregulate efflux pumps that can pump out the cytotoxic agent. For example, resistance to ado-trastuzumab emtansine (T-DXd), an ADC that targets HER2, can occur due to the upregulation of efflux pumps such as ABCB1 and ABCG2.
Activation of DNA damage response pathways:
Cytotoxic agents used in ADCs can induce DNA damage in cancer cells, leading to cell death. However, cancer cells can activate DNA damage response pathways that repair DNA damage and promote cell survival. Resistance to ADCs can occur if cancer cells upregulate DNA damage response pathways that can repair the DNA damage induced by the cytotoxic agent. For example, resistance to gemtuzumab ozogamicin (GO), an ADC that targets CD33, can occur due to the upregulation of DNA damage response pathways such as the ATM/CHK2 pathway.
Tumor microenvironment:
The tumor microenvironment can also contribute to resistance to ADCs. The tumor microenvironment can alter the expression of target antigens, increase the expression of efflux pumps, and activate survival pathways in cancer cells. For example, resistance to T-DM1 can occur due to the presence of stromal cells that secrete factors that activate the PI3K/AKT pathway in cancer cells.
In conclusion, resistance to ADCs can arise through multiple mechanisms, including alterations in the expression or function of the target antigen, changes in the intracellular trafficking and processing of the ADC, activation of survival pathways, efflux of the cytotoxic agent, activation of DNA damage response pathways, and the tumor microenvironment. Understanding the mechanisms of resistance to ADCs is critical for the development of strategies to overcome resistance and improve the efficacy of these promising cancer therapies.
