Browse
Submit Data
Databases
API
Help

Dataset Information

37 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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.

SUBMITTER: de Kort WWB

PROVIDER: S-EPMC7956931 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

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

Project description:IMPORTANCE OF THE FIELD:Recent advances in the understanding of 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. AREAS COVERED IN THIS REVIEW:Books, journals, databases and websites have been searched to provide a current review on the subject. 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. 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.

| S-EPMC3399735 | biostudies-literature

Impact of PI3K/AKT/mTOR pathway activation on the prognosis of patients with head and neck squamous cell carcinomas.

Project description:The PI3K/AKT/mTOR signaling pathway has emerged as one of the most frequently deregulated in head and neck squamous cell carcinomas (HNSCC). Numerous alterations of various upstream and downstream components have been described; however, their prognostic significance and impact on HNSCC patient survival remains to be established. This was addressed using an unbiased cohort of 93 consecutive and homogeneous surgically treated HNSCC patients and results confirmed in 432 HNSCC patients. Our findings reveal the high prevalence of S6 phosphorylation, a surrogate marker of mTORC1 activation, in HNSCC specimens (>70%) and, more importantly, demonstrate its relevance on clinical outcome. Phosphorylation of ribosomal protein S6 on either Ser235/236 or Ser240/244 was consistently and significantly correlated with favorable prognosis, although with differences depending on the tumor site. Thus, p-S6 expression was significantly correlated with better disease-specific survival specifically in the subgroup of laryngeal carcinoma patients (P< 0.001). In addition, multivariate regression models revealed p-S6 to be an inverse and independent predictor of lymph-node metastasis (P= 0.004) and distant metastasis (P= 0.006). Taken together, this study unveils an unprecedented correlation of mTOR activation with improved clinical outcome in patients with laryngeal carcinomas and uncovers the potential of p-S6 expression as a good prognostic biomarker and an inverse predictor of lymph node and distant metastases. These results should be of broad interest as immunohistochemical detection of p-S6 may help to stratify patients and guide treatment decisions.

| S-EPMC5045433 | biostudies-literature

Predictive value of epigenetic alterations in head and neck squamous cell carcinoma.

Project description:Head and neck cancer collectively describes malignant tumors originating from the mucosal surface of the upper aerodigestive tract. These tumors pose a great threat to public health because of their high incidence and mortality. Traditional risk factors are tobacco and alcohol abuse. More recently, infection by high-risk types of human papilloma virus (HPV) has been identified as an additional risk factor, especially for oropharyngeal squamous cell carcinoma (OPSCC). Moreover, HPV-positive OPSCC is considered a distinct tumor entity with an improved clinical outcome compared to HPV-negative OPSCC. Epigenetic alterations act as key events in the pathogenesis of cancer and are of special interest for basic and translational oncology because of their reversible nature. This review provides a comprehensive summary of alterations of the epigenome in head and neck squamous cell carcinoma (HNSCC) with a focus on the methylome (hypomethylation and hypermethylation) and its predictive value in the evaluation of pathologic states and clinical outcome, or monitoring response rates to certain therapies.

| S-EPMC4905189 | biostudies-other

Dual Inhibition of Autophagy and PI3K/AKT/MTOR Pathway as a Therapeutic Strategy in Head and Neck Squamous Cell Carcinoma.

Project description:Genomic analyses of head and neck squamous cell carcinoma (HNSCC) have highlighted alterations in the phosphatidylinositol 3-kinase (PI3K) signaling pathway, presenting a therapeutic target for multiple ongoing clinical trials with PI3K or PI3K/MTOR inhibitors. However, these inhibitors can potentially increase autophagy in HNSCC and indirectly support cancer cell survival. Here, we sought to understand the relationship between the PI3K signaling pathway and autophagy during their dual inhibition in a panel of HNSCC cell lines. We used acridine orange staining, immunoblotting, and tandem sensor Red Fluorescent Protein- Green Fluorescent Protein-, microtubule-associated protein 1 light chain 3 beta (RFP-GFP-LC3B) expression analysis to show that PI3K inhibitors increase autophagosomes in HNSCC cells, but that chloroquine treatment effectively inhibits the autophagy that is induced by PI3K inhibitors. Using the Bliss independence model, we determined that the combination of chloroquine with PI3K inhibitors works in synergy to decrease cancer cell proliferation, independent of the PIK3CA status of the cell line. Our results indicate that a strategy focusing on autophagy inhibition enhances the efficacy of therapeutics already in clinical trials. Our results suggest a broader application for this combination therapy that can be promptly translated to in vivo studies.

| S-EPMC7563873 | biostudies-literature

Identifying Predictive Biomarkers for Head and Neck Squamous Cell Carcinoma Response.

Project description:The 5-year survival rate for head and neck squamous cell carcinoma (HNSCC) is approximately 65%. In addition to radio-chemotherapy, immunotherapy is an approach in the treatment of advanced HNSCC. A better understanding of the immune context would allow personalized treatment by identifying patients who are best suited for different treatment options. In our discovery cohort, we evaluated the expression profiles of CMTM6, PD-L1, CTLA-4, and FOXP3 in 177 HNSCCs from Caucasian patients of all tumor stages and different treatment regimens, correlating marker expression in tumor and immune cells with outcomes. Patients with CMTM6high-expressing tumors had a longer overall survival regardless of treatment. This prognostic benefit of CMTM6 in HNSCC was validated in an independent cohort. Focusing on the in the discovery cohort (n = 177), a good predictive effect of CMTM6high expression was seen in patients receiving radiotherapy (p = 0.07; log rank), but not in others. CMTM6 correlated with PD-L1, CTLA-4 and FOXP3 positivity, with patients possessing CMTM6high/FOXP3high tumors showing the longest survival regardless of treatment. In chemotherapy-treated patients, PD-L1 positivity was associated with longer progression-free survival (p < 0.05). In the 27 patients who received immunotherapy, gene expression analysis revealed lower levels of CTLA-4 and FOXP3 with either partial or complete response to this treatment, while no effect was observed for CMTM6 or PD-L1. The combination of these immunomodulatory markers seems to be an interesting prognostic and predictive signature for HNSCC patients with the ability to optimize individualized treatments.

| S-EPMC10705351 | biostudies-literature

PI3K/AKT/mTOR Signaling Pathway in HPV-Driven Head and Neck Carcinogenesis: Therapeutic Implications.

Project description:High-risk human papillomaviruses (HR-HPVs) are the causal agents of cervical, anogenital and a subset of head and neck carcinomas (HNCs). Indeed, oropharyngeal cancers are a type of HNC highly associated with HR-HPV infections and constitute a specific clinical entity. The oncogenic mechanism of HR-HPV involves E6/E7 oncoprotein overexpression for promoting cell immortalization and transformation, through the downregulation of p53 and pRB tumor suppressor proteins, among other cellular targets. Additionally, E6/E7 proteins are involved in promoting PI3K/AKT/mTOR signaling pathway alterations. In this review, we address the relationship between HR-HPV and PI3K/AKT/mTOR signaling pathway activation in HNC with an emphasis on its therapeutic importance.

| S-EPMC10215516 | biostudies-literature

AXL mediates resistance to PI3K? inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas.

Project description:Phosphoinositide-3-kinase (PI3K)-? inhibitors have shown clinical activity in squamous cell carcinomas (SCCs) of head and neck (H&N) bearing PIK3CA mutations or amplification. Studying models of therapeutic resistance, we have observed that SCC cells that become refractory to PI3K? inhibition maintain PI3K-independent activation of the mammalian target of rapamycin (mTOR). This persistent mTOR activation is mediated by the tyrosine kinase receptor AXL. AXL is overexpressed in resistant tumors from both laboratory models and patients treated with the PI3K? inhibitor BYL719. AXL dimerizes with and phosphorylates epidermal growth factor receptor (EGFR), resulting in activation of phospholipase C? (PLC?)-protein kinase C (PKC), which, in turn, activates mTOR. Combined treatment with PI3K? and either EGFR, AXL, or PKC inhibitors reverts this resistance.

| S-EPMC4398915 | biostudies-literature

Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers.

Project description:Genomic findings underscore the heterogeneity of head and neck squamous cell carcinoma (HNSCC). Identification of mutations that predict therapeutic response would be a major advance. We determined the mutationally altered, targetable mitogenic pathways in a large HNSCC cohort. Analysis of whole-exome sequencing data from 151 tumors revealed the phosphoinositide 3-kinase (PI3K) pathway to be the most frequently mutated oncogenic pathway (30.5%). PI3K pathway-mutated HNSCC tumors harbored a significantly higher rate of mutations in known cancer genes. In a subset of human papillomavirus-positive tumors, PIK3CA or PIK3R1 was the only mutated cancer gene. Strikingly, all tumors with concurrent mutation of multiple PI3K pathway genes were advanced (stage IV), implicating concerted PI3K pathway aberrations in HNSCC progression. Patient-derived tumorgrafts with canonical and noncanonical PIK3CA mutations were sensitive to an mTOR/PI3K inhibitor (BEZ-235), in contrast to PIK3CA-wild-type tumorgrafts. These results suggest that PI3K pathway mutations may serve as predictive biomarkers for treatment selection.

| S-EPMC3710532 | biostudies-literature

Targeting EGFR/PI3K/AKT/mTOR Signaling in Hepatocellular Carcinoma.

Project description:Hepatocellular carcinoma (HCC) poses a significant global health concern, with its incidence steadily increasing. The development of HCC is a multifaceted, multi-step process involving alterations in various signaling cascades. In recent years, significant progress has been made in understanding the molecular signaling pathways that play central roles in hepatocarcinogenesis. In particular, the EGFR/PI3K/AKT/mTOR signaling pathway in HCC has garnered renewed attention from both basic and clinical researchers. Preclinical studies in vitro and in vivo have shown the effectiveness of targeting the key components of this signaling pathway in human HCC cells. Thus, targeting these signaling pathways with small molecule inhibitors holds promise as a potential therapeutic option for patients with HCC. In this review, we explore recent advancements in understanding the role of the EGFR/PI3K/AKT/mTOR signaling pathway in HCC and assess the effectiveness of targeting this signaling cascade as a potential strategy for HCC therapy based on preclinical studies.

| S-EPMC10458925 | biostudies-literature

Biomarker-directed therapy of squamous carcinomas of the head and neck: targeting PI3K/PTEN/mTOR pathway.

Project description: Not available

| S-EPMC5950501 | biostudies-literature