The Role of Tumor-Associated Antigen HER2/neu in Tumor Development and the Different Approaches for Using It in Treatment: Many Choices and Future Directions

SIMPLE SUMMARY: The human epidermal growth factor receptor 2 (HER2) plays a central role in the pathogenesis and development of several types of cancer. For a long time, the overexpression of HER2 by tumor cells was considered a predictor of a poor prognosis, until HER2-targeted therapy was introduced, starting with trastuzumab, which revolutionized the entire field of treatment for HER2-positive cancers and changed their prognosis, with the overexpression of HER2 becoming correlated with increased survival and better outcomes. Since then, this field has undergone tremendous developments, and many new approaches have been implemented, in particular immunotherapy. The purpose of this review is to provide a general understanding of the various approaches for targeting the HER2 molecule for cancer treatment, shedding light on some of the most promising updates in this field. ABSTRACT: The treatment of HER2-positive cancers has changed significantly over the past ten years thanks to a significant number of promising new approaches that have been added to our arsenal in the fight against cancer, including monoclonal antibodies, inhibitors of tyrosine kinase, antibody–drug conjugates, vaccination, and particularly, adoptive-T-cell therapy after its great success in hematological malignancies. Equally important is the new methodology for determining patients eligible for targeted HER2 therapy, which has doubled the number of patients who can benefit from these treatments. However, despite the initial enthusiasm, there are still several problems in this field represented by drug resistance and tumor recurrence that require the further development of new more efficient drugs. In this review, we discuss various approaches for targeting the HER2 molecule in cancer treatment, highlighting their benefits and drawbacks, along with the different mechanisms responsible for resistance to HER2-targeted therapies and how to overcome them.