EGFR–PI3K–AKT–mTOR signaling in head and neck squamous cell carcinomas: attractive targets for molecular-oriented therapy

Abstract

Importance of the field Recent advances in understanding the oncogenesis of head and neck squamous cell carcinomas (HNSCC) have revealed multiple dysregulated signaling pathways. One frequently altered axis is the EGFR/PI3K/Akt/mTOR pathway. This pathway plays a central role in numerous cellular processes including metabolism, cell growth, apoptosis, survival and differentiation, which ultimately contributes to HNSCC progression. What the reader will gain This article reviews the current understanding of EGFR/PI3K/Akt/mTOR signaling in HNSCC, including the impact of both genetic and epigenetic alterations. This review further highlights the potential of targeting this signaling cascade as a promising therapeutic approach in the treatment of HNSCC. Areas covered in this review Books, journals, databases and websites have been searched to provide a current review on the subject. Take home message Genetic alterations of several nodes within this pathway, including both genetic and epigenetic changes, leading to either oncogene activation or inactivation of tumor suppressors, have frequently been implicated in HNSCC. Consequently, drugs that target the central nodes of this pathway have become attractive for molecular oriented cancer therapies. Numerous preclinical and clinical studies are being performed in HNSCC, however, more studies are still needed to better understand the biology of this pathway.

Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck

“…Numerous mutations or alterations in the PI3K pathway have now been identified in human SCCHN, at the level of both gene expression and function (Table 2) [29]. These genes include, but are not limited to: PIK3CA, PIK3CD, PTEN, PDK1, AKT, and mTOR [8,[30][31][32][33][34][35]. Mutations and copy number alterations of PI3K pathway components, including PIK3CA amplifications and PTEN inactivation by loss or inactivation of gene copy, are particularly prevalent in HPV-positive tumors [36].…”

Dysregulation of splicing proteins in head and neck squamous cell carcinoma

“…4,5 Oncogenic activation of PI3K, Notch and hedgehog signaling pathways have been reported in HNSCC and they are being tested in clinical studies as potential targets. [6][7][8] Mass spectrometry-based proteome/phosphoproteome profiling has become a reliable method for studying the signaling pathways/events that are dysregulated in any given system. In this study, we carried out LC-MS/MS analysis of TMT-labeled, titanium dioxide (TiO 2 ) enriched phosphopeptides to study the signaling pathways that are altered in HNSCC cells compared to a normal oral cell line OKF6/TERT1.…”

The functional significance of microRNA-375 in human squamous cell carcinoma: aberrant expression and effects on cancer pathways

“…55 These genes have been used to develop molecularly targeted therapeutic agents for human cancer, such as Gefinitib (Iressa, also known as ZD1839), Erlotinib (marketed as Tarceva) and Cetuximab (marketed as Erbitux), which target epidermal growth factor receptor 56 , and Everolimus (marketed as Afinitor) and Temsirolimus (marketed as Torisel), which target mTOR. 57 Cetuximab received Food and Drug Administration approval for treatment of locally advanced HNSCC in combination with radiotherapy. Overexpression of the genes targeted by these antagonists may result in the reduction of miR-375.…”