Novel ADCs and Strategies to Overcome Resistance to Anti-HER2 ADCs

Simple Summary A proportion of breast tumors bear the oncogenic transmembrane tyrosine kinase protein HER2. Even though therapies that target HER2 have changed the prognosis and quality of life of patients with HER2+ breast tumors, resistance to those therapies is still an important clinical problem. To improve the management of those tumors, a new category of antitumor agents, antibody-drug conjugates (ADCs), has emerged. These agents are created by linking a potent cytotoxic to an antibody that recognizes a membrane protein. Two anti-HER2 ADCs have been approved by the FDA for clinical use and several others are under development. The structure, mechanism of action, and resistance mechanisms to ADCs are reviewed in the present work, as well as potential strategies to overcome resistance to clinically approved anti-HER2 ADCs, including novel anti-HER2 ADCs. During recent years, a number of new compounds against HER2 have reached clinics, improving the prognosis and quality of life of HER2-positive breast cancer patients. Nonetheless, resistance to standard-of-care drugs has motivated the development of novel agents, such as new antibody-drug conjugates (ADCs). The latter are a group of drugs that benefit from the potency of cytotoxic agents whose action is specifically guided to the tumor by the target-specific antibody. Two anti-HER2 ADCs have reached the clinic: trastuzumab-emtansine and, more recently, trastuzumab-deruxtecan. In addition, several other HER2-targeted ADCs are in preclinical or clinical development, some of them with promising signs of activity. In the present review, the structure, mechanism of action, and potential resistance to all these ADCs will be described. Specific attention will be given to discussing novel strategies to circumvent resistance to ADCs.