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Review
. 2023 Jan 16;8(1):31.
doi: 10.1038/s41392-022-01297-0.

Targeted therapy for head and neck cancer: signaling pathways and clinical studies

Qingfang Li #  1 , Yan Tie #  1 , Aqu Alu #  1 , Xuelei Ma  2 , Huashan Shi  3
Affiliations
Review

Targeted therapy for head and neck cancer: signaling pathways and clinical studies

Qingfang Li et al. Signal Transduct Target Ther. .

Abstract

Head and neck cancer (HNC) is malignant, genetically complex and difficult to treat and is the sixth most frequent cancer, with tobacco, alcohol and human papillomavirus being major risk factors. Based on epigenetic data, HNC is remarkably heterogeneous, and treatment remains challenging. There is a lack of significant improvement in survival and quality of life in patients with HNC. Over half of HNC patients experience locoregional recurrence or distal metastasis despite the current multiple traditional therapeutic strategies and immunotherapy. In addition, resistance to chemotherapy, radiotherapy and some targeted therapies is common. Therefore, it is urgent to explore more effective and tolerable targeted therapies to improve the clinical outcomes of HNC patients. Recent targeted therapy studies have focused on identifying promising biomarkers and developing more effective targeted therapies. A well understanding of the pathogenesis of HNC contributes to learning more about its inner association, which provides novel insight into the development of small molecule inhibitors. In this review, we summarized the vital signaling pathways and discussed the current potential therapeutic targets against critical molecules in HNC, as well as presenting preclinical animal models and ongoing or completed clinical studies about targeted therapy, which may contribute to a more favorable prognosis of HNC. Targeted therapy in combination with other therapies and its limitations were also discussed.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Timeline of treatment regimens and targeted therapy development in head and neck cancer and further investigation. Early on, surgery was first used to treat head and neck cancer. With further investigation, more therapies have been used to treat head and neck cancer. In the 1980s, an advanced understanding of HNSCC was made, and some major discoveries were made between the 1980s and 2020s. The prognosis of head and neck cancers was slightly improved but unsatisfactory. Some discoveries might first be made in cancers other than head and neck cancers, and the same discoveries were identified in head and neck cancers after years. More agents were found and approved in head and neck cancers, which may dramatically improve the prognosis of head and neck cancer patients. DNA deoxyribonucleic acid, EGFR epidermal growth factor receptor, HPV human papillomavirus, HNSCC head and neck squamous cell carcinoma, FDA Food and Drug Administration, IMRT intensity modulated radiation therapy
Fig. 2
Fig. 2
The EGFR signaling pathway, PI3K/AKT/mTOR pathway, MAPK pathway, STAT pathway, and MET pathway in head and neck cancer. EGFR epidermal growth factor receptor, TGF-α transforming growth factor-alpha, EGF epidermal growth factor, RTKs receptor tyrosine kinases, HER2/3 human epidermal growth factor receptor 2/3, c-MET c‑mesenchymal–epithelial transition factor, IGF-1R insulin-like growth factor 1 receptor, PGE2 prostaglandin E2, GPCR G-protein-coupled receptor, PLCγ phospholipase c-γ, PKC protein kinase C, JAK Jenus-activated kinase; STAT3/5, signal transducer and activator of transcription 3/5, PTEN phosphatase and tensin homolog, PI3K phosphoinositide 3-kinase, PIP2 phosphatidylinositol 4,5-bisphosphate, PIP3 phosphatidylinositol 3,4,5-trisphosphate, AKT serine/threonine-specific protein kinase, mTOR mammalian target of rapamycin, DNMT-1 DNA methyltransferase 1, SOS son of sevenless, GRB2 growth factor receptor-bound protein 2, SHC SRC homology domain c-terminal adaptor homolog, ERK: extracellular signal-regulated kinase, MAP2K6 mitogen-activated protein kinase–kinase 6, PAK1 p21-activated kinase 1, DUSP dual-specificity phosphatases, PCNA proliferation cell nuclear antigen, DNA-PK DNA-dependent protein kinase
Fig. 3
Fig. 3
The p53 signaling pathway and NF-κB pathway in head and neck cancer. CHK1/2 cell cycle checkpoint kinase 1/2, MDM2 murine double minute 2, CDK cyclin-dependent kinase, RB retinoblastoma, TNF tumor necrosis factor, TNFR tumor necrosis factor receptor, TLR4 Toll-like receptor 4, TRAF TNFR-associated factor, RIP receptor-interacting protein, IKK IκB kinase
Fig. 4
Fig. 4
Wnt/β-catenin signaling pathway, Notch pathway, NRF2 pathway, Hippo pathway, and Sonic Hedgehog pathway in head and neck cancer. Fzd frizzled receptor, Lrp receptor-related protein coreceptor, Dvl disheveled, CK1 casein kinase 1, GSK-3β glycogen synthase kinase 3β, APC adenomatous polyposis coli, TCF/LEF T-cell factor/lymphoid enhancing factor, Dll 1/3/4 Delta-like family, HES1 hairy and enhancer of split 1, NRF2, nuclear factor erythroid 2-related factor 2, KEAP1 Kelch-like ECH-associated protein 1, CUL3 cullin-3, ARE antioxidant-responsive elements, YAP yes-associated protein, TAZ transcriptional coactivator with PDZ-binding motif
Fig. 5
Fig. 5
Comprehensive understanding and inhibitor direction for targeting signaling pathways in preclinical HNC treatment. EGFR epidermal growth factor receptor, EGF epidermal augmentum factor, MET mesenchymal–epithelial transition factor, JAK Janus-activated kinase, STAT signal transducer and activator of transcription, AKT serine/threonine-specific protein kinase, mTOR mammalian target of rapamycin, CDK cyclin-dependent kinase, VEGF vascular endothelial growth factor, mAb monoclonal antibody, RET rearranged during transfection, p phosphorylation
Fig. 6
Fig. 6
Comprehensive understanding and inhibitor direction for targeting signaling pathways in clinical trials in HNC treatment. EGFR epidermal growth factor receptor, MET mesenchymal–epithelial transition factor, AKT serine/threonine-specific protein kinase, mTOR mammalian target of rapamycin, CDK cyclin-dependent kinase, VEGF vascular endothelial growth factor, JAK jenus-activated kinase, STAT signal transducer and activator of transcription, mAb monoclonal antibody, RET rearranged during transfection, p phosphorylation
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