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Review
. 2023 Feb 2:10:1066021.
doi: 10.3389/fmed.2023.1066021. eCollection 2023.

Recent findings on the impact of ErbB receptors status on prognosis and therapy of head and neck squamous cell carcinoma

Camilla Palumbo  1 , Monica Benvenuto  1   2 , Chiara Focaccetti  1 , Loredana Albonici  1 , Loredana Cifaldi  1   3 , Alessandra Rufini  2   4 , Daniela Nardozi  5 , Valentina Angiolini  5 , Arianna Bei  6 , Laura Masuelli  5 , Roberto Bei  1
Affiliations
Review

Recent findings on the impact of ErbB receptors status on prognosis and therapy of head and neck squamous cell carcinoma

Camilla Palumbo et al. Front Med (Lausanne). .

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type, has often an aggressive course and is poorly responsive to current therapeutic approaches, so that 5-year survival rates for patients diagnosed with advanced disease is lower than 50%. The Epidermal Growth Factor Receptor (EGFR) has emerged as an established oncogene in HNSCC. Indeed, although HNSCCs are a heterogeneous group of cancers which differ for histological, molecular and clinical features, EGFR is overexpressed or mutated in a percentage of cases up to about 90%. Moreover, aberrant expression of the other members of the ErbB receptor family, ErbB2, ErbB3 and ErbB4, has also been reported in variable proportions of HNSCCs. Therefore, an increased expression/activity of one or multiple ErbB receptors is found in the vast majority of patients with HNSCC. While aberrant ErbB signaling has long been known to play a critical role in tumor growth, angiogenesis, invasion, metastatization and resistance to therapy, more recent evidence has revealed its impact on other features of cancer cells' biology, such as the ability to evade antitumor immunity. In this paper we will review recent findings on how ErbB receptors expression and activity, including that associated with non-canonical signaling mechanisms, impacts on prognosis and therapy of HNSCC.

Keywords: Cetuximab; EGFR; ErbB receptors; head and neck squamous cell carcinoma; immune checkpoint inhibitors.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The ErbB/HER family of receptor tyrosine kinases includes four members: EGFR (HER1, ErbB1), ErbB2, ErbB3, and ErbB4 (HER2-4). After the binding with the cognate ligands, ErbB receptors form homo- and heterodimers/oligomers in various combinations. This leads to receptor trans/autophosphorylation and the activation of signaling cascades, resulting in proliferation, differentiation, cell motility, and cell death inhibition. Several ligands have been described, including Epidermal Growth Factor (EGF), Transforming Growth Factor-alpha (TGF-α), Amphiregulin (AR), Betacellulin (BTC), Heparin Binding Epidermal Growth Factor (HB-EGF), Epiregulin (EPR), and Neuregulins (NRGs). The specific ligands for EGFR are EGF, TGF-α and AR. NRG1-2 bind to ErbB3. BTC, HB-EGF, EPR, NRG1-4 bind to ErbB4. BTC, HB-EGF and EPR can also bind to EGFR. ErbB2, which does not have a direct ligand, and ErbB3, which has impaired kinase activity, signal via heterodimerization with other members of the family. Moreover, spontaneous dimerization of ErbB2 can occur due to the receptor overexpression. EGFR can also form heterodimers with receptor tyrosine kinases that do not belong to the ErbB family, such as the HGF receptor Met.
Figure 2
Figure 2
Non-canonical signaling by nuclear EGFR. EGFR nuclear translocation is known to be induced by ligand binding as well as by cell exposure to radiations, drugs and EGFR-targeting agents. The known oncogenic functions of nuclear EGFR include: phosphorylation and stabilization of chromatin-bound PCNA, which in turn plays an essential role in DNA replication and repair; promotion of DNA repair via protein–protein interaction with the DNA-dependent protein kinase (DNA-PK); co-activation of transcription via the interaction with different transcriptional regulators. The interaction between nuclear EGFR and RNA helicase A (RHA) leads to an enhanced expression of cyclin D1. Among the other genes whose expression is enhanced by nuclear EGFR, in association with various transcription factors, are those encoding for c-Myc, B-Myb, Aurora Kinase A and thymidylate synthase.
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