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EGFR and RB1 as Dual Biomarkers in HPV-Negative Head and Neck Cancer
Journal article   Open access   Peer reviewed

EGFR and RB1 as Dual Biomarkers in HPV-Negative Head and Neck Cancer

Tim N Beck, Rachel Georgopoulos, Elena I Shagisultanova, David Sarcu, Elizabeth A Handorf, Cara Dubyk, Miriam N Lango, John A Ridge, Igor Astsaturov, Ilya G Serebriiskii, …
Molecular cancer therapeutics, v 15(10), pp 2486-2497
Oct 2016
DOI: https://doi.org/10.1158/1535-7163.MCT-16-0243
PMID: 27507850
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://mct.aacrjournals.org/content/molcanther/15/10/2486.full.pdfView
Published, Version of Record (VoR) Open
url
https://doi.org/10.1158/1535-7163.MCT-16-0243View
Published, Version of Record (VoR) Open

Abstract

Adult Aged Aged, 80 and over Biomarkers, Tumor Cyclin-Dependent Kinase 4 - antagonists & inhibitors Cyclin-Dependent Kinase 6 - antagonists & inhibitors Female Head and Neck Neoplasms - diagnosis Head and Neck Neoplasms - etiology Head and Neck Neoplasms - metabolism Head and Neck Neoplasms - surgery Humans Immunohistochemistry Kaplan-Meier Estimate Male Middle Aged Models, Biological Neoplasm Staging Papillomaviridae Papillomavirus Infections - complications Papillomavirus Infections - virology Phosphorylation Prognosis Protein Kinase Inhibitors - pharmacology Receptor, Epidermal Growth Factor - genetics Receptor, Epidermal Growth Factor - metabolism Receptor, ErbB-2 - antagonists & inhibitors Retinoblastoma Binding Proteins - genetics Retinoblastoma Binding Proteins - metabolism Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism
Clinical decision making for human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is predominantly guided by disease stage and anatomic location, with few validated biomarkers. The epidermal growth factor receptor (EGFR) is an important therapeutic target, but its value in guiding therapeutic decision making remains ambiguous. We integrated analysis of clinically annotated tissue microarrays with analysis of data available through the TCGA, to investigate the idea that expression signatures involving EGFR, proteins regulating EGFR function, and core cell-cycle modulators might serve as prognostic or drug response-predictive biomarkers. This work suggests that consideration of the expression of NSDHL and proteins that regulate EGFR recycling in combination with EGFR provides a useful prognostic biomarker set. In addition, inactivation of the tumor suppressor retinoblastoma 1 (RB1), reflected by CCND1/CDK6-inactivating phosphorylation of RB1 at T356, inversely correlated with expression of EGFR in patient HNSCC samples. Moreover, stratification of cases with high EGFR by expression levels of CCND1, CDK6, or the CCND1/CDK6-regulatory protein p16 (CDKN2A) identified groups with significant survival differences. To further explore the relationship between EGFR and RB1-associated cell-cycle activity, we evaluated simultaneous inhibition of RB1 phosphorylation with the CDK4/6 inhibitor palbociclib and of EGFR activity with lapatinib or afatinib. These drug combinations had synergistic inhibitory effects on the proliferation of HNSCC cells and strikingly limited ERK1/2 phosphorylation in contrast to either agent used alone. In summary, combinations of CDK and EGFR inhibitors may be particularly useful in EGFR and p RB1-expressing or CCND1/CDK6-overexpressing HPV-negative HNSCC. Mol Cancer Ther; 15(10); 2486-97. ©2016 AACR.

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Web of Science research areas
Oncology
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