Elsevier

Cancer Treatment Reviews

Volume 109, September 2022, 102436
Cancer Treatment Reviews

Beyond HER2: Targeting the ErbB receptor family in breast cancer

https://doi.org/10.1016/j.ctrv.2022.102436Get rights and content

Highlights

  • Prior efforts to target the ErbB receptor family beyond HER2 have been inadequate.

  • Novel therapeutic approaches such as antibody-drug conjugates hold promise.

  • Better patient selection can improve the potential of these agents in breast cancer.

Abstract

Targeting the HER2 oncogene represents one of the greatest advances in the treatment of breast cancer. HER2 is one member of the ERBB-receptor family, which includes EGFR (HER1), HER3 and HER4. In the presence or absence of underling genomic aberrations such as mutations or amplification events, intricate interactions between these proteins on the cell membrane lead to downstream signaling that encourages cancer growth and proliferation. In this Review, we contextualize efforts to pharmacologically target the ErbB receptor family beyond HER2, with a focus on EGFR and HER3. Preclinical and clinical efforts are synthesized. We discuss successes and failures of this approach to date, summarize lessons learned, and propose a way forward that invokes new therapeutic modalities such as antibody drug conjugates (ADCs), combination strategies, and patient selection through rational biomarkers.

Introduction

The ErbB family is comprised of four transmembrane growth factor receptors which are closely related: EGFR (or HER1), HER2, HER3 and HER4 [1]. These proteins are critical for the development of normal cells, but when dysregulated, can promote disordered proliferation, invasion, and unchecked cell survival leading to the development of cancer [2]. Intricate and complex interactions between these receptors, in the presence or absence of extracellular ligands, results in activation of downstream signaling primarily via the PI3K/AKT, MAP kinase, and JAK/STAT pathways [3], [4] (Fig. 1). Such aberrant signaling is typically caused by mutations or amplification of ErbB family genes, leading to increased homo- or hetero-dimerization and constitutively active kinase activity with resultant downstream signaling [4]. A high-level structural homology exists between members of the ErbB receptor family, with an extracellular ligand binding domain, a transmembrane helix and a cytoplasmic domain which possesses enzymatic activity. However, notable exceptions include the fact that HER2 does not have a direct ligand and HER3 has impaired kinase activity [5]. Interactions between these proteins on the cell surface are highly interrelated, forming a complex signaling network where no individual member functions in isolation, and cooperation is the rule rather than the exception [6].

In breast cancer, 15–20% of tumors specifically overexpress HER2 due to ERBB2 gene amplification, resulting in a cancer phenotype that is highly aggressive if left untreated [7]. The capability to pharmacologically target the HER2 oncoprotein represents one of the great triumphs of oncologic science, and has transformed the prognosis of this this disease, resulting in meaningful improvements in overall survival for patients with early or advanced HER2-positive breast cancers, as reviewed elsewhere [8]. Given the intricate relationships between the four ErbB family members in their individual/collective contribution to oncogenesis, renewed interest has arisen in how these interactions can be harnessed to improve upon the tissue specificity and cytotoxicity of existing therapies. In this review, we focus on how targeting ErbB proteins beyond HER2, including epidermal growth factor receptor (EGFR), HER3, and HER4 might improve outcomes for patients with breast cancer. We briefly review historical attempts to target these proteins as well as novel strategies, including monoclonal antibodies (mABs), tyrosine kinase inhibitors (TKIs) and antibody drug conjugates (ADCs) (see Table 1, Table 2).

Section snippets

Egfr (HER1)

EGFR, one of the most canonical oncogenes in cancer medicine, is encoded by the EGFR gene on chromosome 7p11, and was identified first in the 1970s [9]. Known ligands of EGFR are numerous, and include EGF, TGF-alpha, and amphiregulin, among several others [10]. In the presence or absence of a ligand, the major heterodimerization partner for EGFR is HER2. When paired, EGFR and HER2 form stable activated complexes, which are endocytosed at a slow rate and readily recycled to the cell surface

Her3

HER3 is encoded by the ERBB3 gene, located on chromosome 12q13; known ligands for this receptor include NRG-1 and NRG-2 [44]. Of special note, HER3 does not possess kinase activity on its own, however it is capable of forming heterodimers with HER2 (and/or EGFR), which dramatically increases transphosphorylation and activation of downstream signaling cascades, in perhaps the most mitogenic stimulus in human breast cancer [44], [45]. Moreover HER3 stands out among ErbB family members as a potent

Her4

The ERBB4 gene is located on chromosome 22q33; known ligands of HER4 include neuregulins and epiregulin, among others [44], [70]. The role of HER4 in cancer development and signaling is a complex one, with many unanswered questions. HER4 is capable of homodimerization or heterodimerization, which may have contrasting effects on cell proliferation and survival. Some studies have shown a positive correlation between ERBB4 expression and breast cancer related outcomes [18], [71], [72], in that

A note on toxicity

EGFR, HER2, HER3 and HER4 are expressed widely in normal tissues, and play a major role in physiologic cell processes. Specifically, EGFR is expressed in the skin, gastrointestinal system, and kidney [80]; HER2 is expressed in the gastrointestinal, respiratory, reproductive tract, skin, breast, placenta, and heart [81]; HER3 is found at high levels in the gastrointestinal tract and central nervous system [82], and HER4 is found in skeletal muscle, heart, and central nervous system [70].

Future directions

To date, targeting EGFR, HER3 or HER4 in breast cancer with monoclonal antibodies or small molecule inhibitors has unfortunately born little fruit. This is most likely due to the complexity of interactions between the ErbB receptor family members as well as their downstream signaling cascades, which, besides HER2, function largely in a network fashion rather than as singular oncogenes in breast cancer. With some examples discussed above, it is quite possible that biomarkers can select the

Conclusion

Despite many setbacks, strategies targeting ErbB proteins beyond HER2 still hold promise, particularly those which take advantage of new drug delivery platforms and biomarker selection. Herein, we highlight the progress and pitfalls of these efforts to date. Promising strategies include the use of ADCs and monoclonal or bispecific antibodies, and future studies would likely benefit from using biomarker selection in order to better balance the benefits of these drugs against their known

CRediT authorship contribution statement

Joshua Z. Drago: Conceptualization, Project administration, Visualization, Writing – original draft. Emanuela Ferraro: Data curation, Formal analysis, Investigation, Validation, Visualization, Writing – review & editing. Nour Abuhadra: Visualization, Writing – review & editing. Shanu Modi: Conceptualization, Supervision, Writing – review & editing.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

All authors acknowledge support from the NCI Cancer Center Support Grant P30-CA008748. J.Z.D. acknowledges support from the Paul Calabresi Career Development Award for Clinical Oncology K12 CA184746.

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