Predictive Value of EGFR-PI3K-AKT-mTOR-Pathway Inhibitor Biomarkers for Head and Neck Squamous Cell Carcinoma: A Systematic Review

Abstract

Background Understanding molecular pathogenesis of head and neck squamous cell carcinomas (HNSCC) has considerably improved in the last decades. As a result, novel therapeutic strategies have evolved, amongst which are epidermal growth factor receptor (EGFR)-targeted therapies. With the exception of cetuximab, targeted therapies for HNSCC have not yet been introduced into clinical practice. One important aspect of new treatment regimes in clinical practice is presence of robust biomarkers predictive for therapy response. Methods We performed a systematic search in PubMed, Embase and the Cochrane library. Articles were included if they investigated a biomarker for targeted therapy in the EGFR-PI3K-AKT-mTOR-pathway. Results Of 83 included articles, 52 were preclinical and 33 were clinical studies (two studies contained both a preclinical and a clinical part). We classified EGFR pathway inhibitor types and investigated the type of biomarker (biomarker on epigenetic, DNA, mRNA or protein level). Conclusion Several EGFR-PI3K-AKT-mTOR-pathway inhibitor biomarkers have been researched for HNSCC but few of the investigated biomarkers have been adequately confirmed in clinical trials. A more systematic approach is needed to discover proper biomarkers as stratifying patients is essential to prevent unnecessary costs and side effects. Supplementary Information The online version contains supplementary material available at 10.1007/s40291-021-00518-6.

Multi-omics analysis to screen potential therapeutic biomarkers for anti-cancer compounds

“…Here we presented the evidence of the predictive value of therapeutic biomarkers, e.g., EGFR for BLCA and HNSC, TERT for HNSC and MESO. Although few conformed in clinical trials, several EGFR-pathway inhibitor biomarkers still been researched for HNSC, and the predictive value is obvious to all 48 . We also note that EGFR can be used as a prognostic biomarker in BLCA due to the significant association of EGFR overexpression with tumor grade, muscularis propria invasion and recurrence 49 .…”

Shooting at Moving and Hidden Targets—Tumour Cell Plasticity and the Notch Signalling Pathway in Head and Neck Squamous Cell Carcinomas

“…EGFR signalling has become a key pathway for targeted therapies for HNSCC [ 130 ]. Presently, and despite some considerable side effects [ 59 ], the most advanced and characterized EGFR inhibitor is Cetuximab .…”

“…Mechanistically, cetuximab blocks the extracellular domain of EGFR dimers, located at the plasma membrane, inhibits its signalling, and leads to rapid receptor internalization. Additionally, upon binding to the receptor, Cetuximab potently induces antibody-dependent cellular cytotoxicity, resulting in subsequent destruction of the tumour cells [ 130 ]. Cetuximab has also been shown to reduce the secretion of pro-angiogenic factors such as VEGF (vascular endothelial growth factor), but its use for therapeutic inhibition of angiogenesis at least in monotherapy is questionable [ 131 ].…”

“…The EGFR pathway is also a target for a broad panel of receptor tyrosine kinase inhibitors ( RTKIs ) such as Afatinib , Allitinib , Dacomitinib , Erlotinib , Gefitinib , Lapatinib , or Sorafenib . These are low-molecular weight molecules that bind to the intracellular protein domains of EGFR, where they block phosphorylation and therefore signal transduction [ 130 ]. In addition to EGFR, some RTKIs also target other members of the ERBB tyrosine kinase receptor superfamilies, such as ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4) [ 152 ].…”

MiRNome analysis identifying miR‐205 and miR‐449a as biomarkers of disease progression in intestinal‐type sinonasal adenocarcinoma

“…The molecular events involved in the pathogenesis of ITAC 12 , 13 , 14 , 15 , 16 are not fully known despite the increasing information about the molecular mechanisms involved in the pathogenesis of head and neck squamous cell carcinomas (HNSCC). 17 , 18 , 19 , 20 , 21 Overall, few recurrent gene mutations have been noted in sinonasal adenocarcinoma. The most frequently demonstrated is KRAS gene mutation, which has been detected in 12%–43% of cases, with a potential link to wood‐dust‐associated carcinogenesis.…”