Neu Perspectives, Therapies, and Challenges for Metastatic HER2-Positive Breast Cancer

Abstract

Even though gene amplification or protein overexpression occurs in approximately one-fifth of all breast cancers, the discovery of HER2 has, nevertheless, had profound implications for the disease. Indeed, the characterization of the receptor resulted in a number of significant advances. Structurally, unique features provided avenues for the development of numerous compounds with target-specificity; molecularly, biological constructs revealed a highly complex, internal signal transduction pathway with regulatory effects on tumor proliferation, survival, and perhaps, even resistance; and clinically, disease outcomes manifested its predictive and prognostic value. Yet despite the receptor's utility, the beneficial effects are diminished by tumor recurrence after neo- or adjuvant therapy as well as losses resulting from the inability to cure patients with metastatic disease. What these observations suggest is that while tumor response may be partially linked to uncoupling cell surface message reception and nuclear gene expression, as well as recruitment of the innate immune system, disease progression and/or resistance may involve a reprogrammable signaling mainframe that elicits alternative growth and survival signals. This review attempts to meld current perceptions related to HER2-positive metastatic breast cancer with particular attention to current biological insights and therapeutic challenges.

Keywords: ErbB; Fam-trastuzumab deruxtecan; HER2; PHESGO; ado-trastuzumab emtansine; lapatinib; margetuximab; neratinib; neu; pertuzumab; trastuzumab; tucatinib.

Figure 1

Pictorial rendition of p185^HER2. Distal to the amino terminus, the extracellular region consists of four distinct sectors; two ligand-binding domains (L-B1 and L-B2) and two flanking cysteine-rich domains (C-R1 and C-R2), join to a short membrane-spanning region which connects with the intracellular catalytic kinase domain (TK). Sites of receptor phosphorylation are embedded in the TK region and along the carboxy terminus (denoted by P).

Figure 2

Schematic adaptation of major components of the HER-signaling pathway. Ligand binding is believed to prompt dimerization initially followed by phosphorylated-activation of the receptors. The simple construct depicted by the linear alignment of the cytoplasmic components enshrouds a highly complex network responsible for transmitting externally derived stimuli to the internal nuclear apparatus. The ultimate cellular response depends on signal propagation which can be influenced by feedback loops, inter-pathway communications, pro- and counter-regulatory proteins as well as somatic kinase mutations. The RAS pathway is complicated as the kinase is a GTP-binding protein which must undergo post-translational modification before it can be activated. Binding of RAS to phospho-HER2 requires two adaptor molecules, Shc and GRB2. The latter forms a complex with SoS which is recruited to the plasma membrane leading to activation of RAS. Downstream effectors of the RAS signal transduction pathway include soluble RAF, MEK, ERK1/2, and SEK. Translocation of ERK1/2 upregulates c-Myc and Elk-1; Elk-1 is a transcription factor that activates c-Fos, a nuclear proto-oncogene that modulates expression of cyclin-dependent kinases. A second major signaling pathway includes PI3K which is activated by binding preferentially to phospho-HER3. Extracellular signal propagation involves AKT, mTOR, and S6K, three intrinsic elements, with outreach that can influence apoptosis, angiogenesis, cell migration, cell cycle and even other receptor signaling pathways including ER. Of biological and [potential] clinical importance is the finding that ER can contribute HER2 resistance by downregulating HER2 expression and upregulating expression of IGFR1. Furthermore, by interacting with receptor-bound HER2, ER can also activate the MAPK signaling pathway which may be one mechanism of endocrine resistance. Interestingly, AKT appears to be a key regulator of ER gene transcription via interactions with FOXO3a and NFκB.

Figure 3

Putative mechanisms of resistance to HER2-directed therapies. HER2 homo- and hetero-dimers activate key signaling pathways. Mutations involving the PI3K/AKT/TORC and RAS/MEK/MAPK pathways, as well as loss of PTEN promote tumor cell growth and survival. Certain Fc receptor subtypes, such as FcγRIIB, or polymorphisms lower antibody binding affinity. HSP90 impairs endocytosis of the trastuzumab-HER2 complex. Upregulation of inhibitory receptors in the tumor microenvironment impair anti-tumor immune responses. Cyclin D1-overexpressing tumors demonstrate reduced responsiveness to trastuzumab-based therapy. Overexpression of cyclin D1 reduces responsiveness to trastuzumab-based therapy. ADAM10 cleaves the extracellular domain of HER2 resulting in a constitutively active truncated receptor. The MUC4 protein interferes with trastuzumab binding through epitope masking. Drug efflux pumps like ABC transporters can also reduce efficacy to HER2-targeted therapies.