Novel Therapies and Strategies to Overcome Resistance to Anti-HER2-Targeted Drugs

SIMPLE SUMMARY: Drug resistance is the “Achilles’ heel” in current oncology. In this sense, the clinical management of HER2 breast carcinomas (tumors with overexpression/amplification of the ErbB2/HER2 oncogene) is still a challenge. Although a variety of anti-HER2 therapies (anti-HER2 antibodies, antibody–drug conjugates, and tyrosine kinase inhibitors) are available for these patients, the frequent appearance of innate and acquired tumor resistance to these treatments creates an urgent need to develop new and more effective therapeutic approaches. In this review, we discuss the most relevant clinical and pre-clinical advances in therapeutic strategies aimed at overcoming drug resistance in HER2 breast cancer patients in different stages of the disease. ABSTRACT: The prognosis and quality of life of HER2 breast cancer patients have significantly improved due to the crucial clinical benefit of various anti-HER2 targeted therapies. However, HER2 tumors can possess or develop several resistance mechanisms to these treatments, thus leaving patients with a limited set of additional therapeutic options. Fortunately, to overcome this problem, in recent years, multiple different and complementary approaches have been developed (such as antibody–drug conjugates (ADCs)) that are in clinical or preclinical stages. In this review, we focus on emerging strategies other than on ADCs that are either aimed at directly target the HER2 receptor (i.e., novel tyrosine kinase inhibitors) or subsequent intracellular signaling (e.g., PI3K/AKT/mTOR, CDK4/6 inhibitors, etc.), as well as on innovative approaches designed to attack other potential tumor weaknesses (such as immunotherapy, autophagy blockade, or targeting of other genes within the HER2 amplicon). Moreover, relevant technical advances such as anti-HER2 nanotherapies and immunotoxins are also discussed. In brief, this review summarizes the impact of novel therapeutic approaches on current and future clinical management of aggressive HER2 breast tumors.