The root cause of drug resistance in HER2-positive breast cancer and the therapeutic approaches to overcoming the resistance

Abstract

HER2 is a well-known oncogenic receptor tyrosine kinase. HER2 gene amplification occurs in about 20% of breast cancer (BC), which leads to overexpression of HER2 protein, known as HER2-positive BC. Inhibitors of HER2 have significantly improved the prognosis of patients with this subset of BC. Since 1998, seven HER2 inhibitors have been developed to treat this disease. However, drug resistance is common and remains a major unresolved clinical problem. Patients typically show disease progression after some time on treatment. This review discusses the complexity and diversified nature of HER2 signaling, the mechanisms of actions and therapeutic activities of all HER2 inhibitors, the roles of HER2 and other signaling proteins in HER2-positive BC resistant to the inhibitors, the non-cell-autonomous mechanisms of drug resistance, and the heterogeneity of tumor HER2 expression. The review presents the concept that drug resistance in HER2-positive BC results primarily from the inability of HER2 inhibitors to deplete HER2. Emerging therapeutics that are promising for overcoming drug resistance are also discussed.

Keywords: Cancer treatment; HER2 inhibitor; PEPD(G278D); Receptor tyrosine kinase; Targeted therapy; Therapeutic resistance.

Fig. 1

Highly diversified oncogenic signaling of HER2 in HER2-positive BC cells. Overexpressed HER2 in cell membrane gives rise to p95HER2 via ECD shedding, forms ligand-independent homodimeric signaling unit, and forms heterodimeric signaling units with a large number of RTKs, many of which have been implicated in drug resistance in HER2-positive BC. The vast signaling network activates various oncogenic signaling pathways. HER2 oncogenic activity is further enhanced by heterodimerization with non-RTK cell surface proteins, including CB₂R, MUC1, and MUC4. Overexpressed HER2 also translocates to the nucleus and mitochondria to further diversify its oncogenic signaling. The ovals with numbers in HER2 represent sub-extracellular domains, and the yellow oval represents tyrosine kinase domain. The brown oval indicates tyrosine kinase activation.

Fig. 2

Mechanisms of actions of clinically available HER2 inhibitors. A. Trastuzumab and pertuzumab targets HER2 by binding to ECD subdomains 4 and 2, respectively. Both T-DM1 and DS-8201a retain the therapeutic activities of trastuzumab, but delivery of their chemotherapy payloads requires HER2-mediated internalization and release of their payloads via cleavage by lysosome enzymes. B. Inhibition of tyrosine kinase activities of HER family members by lapatinib, neratinib and tucatinib. The hatched oval in HER3 indicates that its tyrosine kinase is severely impaired.

Fig. 3

The impact of PEPD or PEPD^G278D on HER2, EGFR, and HER2 heterodimers. A. PEPD or PEPD^G278D forms a tetramer with HER2 or EGFR by binding to ECD subdomain 3 of HER2 and ECD subdomain 2 of EGFR, which leads to internalization and lysosomal degradation of the RTKs. B. PEPD or PEPD^G278D disrupts the heterodimers of HER2-EGFR, HER2-HER3, HER2-IGF1R, HER2-MET, and HER2-MUC4 by forcing HER2 homodimerization and EGFR homodimerization. The PEPD- or PEPD^G278D-bound homodimers of HER2 and EGFR are then internalized and degraded. This causes inactivation of all the RTKs. The intracellular kinase domains are indicated with an oval or bar, and the hatched oval in HER3 indicates impaired kinase. The dimmed color in the kinase domains of HER3, IGF1R and MET indicates loss of phosphorylation and inactivation.