Novel Therapies to Overcome HER2 Therapy Resistance in Breast Cancer

Abstract

Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that is overexpressed in approximately 15–20% of breast cancers. Trastuzumab was the first HER2-targeted therapy to be approved for clinical use against HER2-overexpressing metastatic breast cancer. However, some patients fail to respond, and many eventually develop progressive disease despite receiving treatment, which may be attributed to the development of a resistant phenotype. New therapies have been developed and approved in combination with trastuzumab for newly diagnosed disease. However, this combinatory regimen also fails and leads to treatment resistance. In this chapter, we review currently used HER2-targeted therapies for breast cancer, available therapies for HER2 antibody therapy-resistant breast cancer, and molecular mechanisms that contribute to the development of resistance. The primary focus is on novel approaches to overcome HER2 therapy resistance in the treatment of breast cancer. We discuss approaches to target HER2 with antibodies, tyrosine kinase inhibitors, or antibody-drug conjugates, as well as targeting downstream signaling, immune pathways, cell cycle regulators, and estrogen receptor signaling. Ultimately, this chapter will provide a detailed overview of the mechanisms of resistance in HER2-positive breast cancers and therapeutic strategies for patients who have developed progressive disease while being treated with HER2 antibody therapy.