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

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.

Keywords: HER2 breast cancer; antiHER2 therapies; resistance.

Figure 1

Current established treatment protocol for early-stage, advanced, or metastatic HER2 BC according to ASCO and NCCN guidelines. The different treatment options for each stage are presented sequentially based on their strength of recommendation. Icons designed with smart.servier.com and Adobe Illustrator.

Figure 2

Overview of the novel therapeutic strategies to overcome resistance to anti-HER2 therapies in HER2 BC (highlighted in red). The figure includes the therapies under clinical validation, including novel anti-HER2 drugs (novel TKIs, antibodies, ADCs, CAR-T cells, etc.), immunotherapies, CDK4/6 inhibitors, PI3K/AKT/mTOR inhibitors, endocrine therapy, Hsp90 and HDAC inhibitors, other RTKs inhibitors, non-receptor tyrosine kinase inhibitors, FASN inhibitors, and PARP inhibitors. Furthermore, novel approaches under preclinical validation are also pointed out, such as nanotherapy, inhibition of pro-survival autophagy, and targeting of HER2 amplicon genes (e.g., GSDMB). Icons designed with smart.servier.com and Adobe Illustrator.