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Phosphoproteomic analysis of signaling pathways in head and neck squamous cell carcinoma patient samples.

ABSTRACT: Molecular targeted therapy represents a promising new strategy for treating cancers because many small-molecule inhibitors targeting protein kinases have recently become available. Reverse-phase protein microarrays (RPPAs) are a useful platform for identifying dysregulated signaling pathways in tumors and can provide insight into patient-specific differences. In the present study, RPPAs were used to examine 60 protein end points (predominantly phosphoproteins) in matched tumor and nonmalignant biopsy specimens from 23 patients with head and neck squamous cell carcinoma to characterize the cancer phosphoproteome. RPPA identified 18 of 60 analytes globally elevated in tumors versus healthy tissue and 17 of 60 analytes that were decreased. The most significantly elevated analytes in tumor were checkpoint kinase (Chk) 1 serine 345 (S345), Chk 2 S33/35, eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) S65, protein kinase C (PKC) ?/? threonine 410/412 (T410/T412), LKB1 S334, inhibitor of kappaB alpha (I?B-?) S32, eukaryotic translation initiation factor 4E (eIF4E) S209, Smad2 S465/67, insulin receptor substrate 1 (IRS-1) S612, mitogen-activated ERK kinase 1/2 (MEK1/2) S217/221, and total PKC ?. To our knowledge, this is the first report of elevated PKC ? in head and neck squamous cell carcinoma that may have significance because PKC ? is an oncogene in several other tumor types, including lung cancer. The feasibility of using RPPA for developing theranostic tests to guide personalized therapy is discussed in the context of these data.

SUBMITTER: Frederick MJ

PROVIDER: S-EPMC3070553 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Phosphoproteomic analysis of signaling pathways in head and neck squamous cell carcinoma patient samples.

Frederick Mitchell J MJ VanMeter Amy J AJ Gadhikar Mayur A MA Henderson Ying C YC Yao Hui H Pickering Curtis C CC Williams Michelle D MD El-Naggar Adel K AK Sandulache Vlad V Tarco Emily E Myers Jeffrey N JN Clayman Gary L GL Liotta Lance A LA Petricoin Emanuel F EF Calvert Valerie S VS Fodale Valentina V Wang Jing J Weber Randal S RS

The American journal of pathology 20110201 2

Molecular targeted therapy represents a promising new strategy for treating cancers because many small-molecule inhibitors targeting protein kinases have recently become available. Reverse-phase protein microarrays (RPPAs) are a useful platform for identifying dysregulated signaling pathways in tumors and can provide insight into patient-specific differences. In the present study, RPPAs were used to examine 60 protein end points (predominantly phosphoproteins) in matched tumor and nonmalignant b ...[more]

PMID: 21281788

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Project description:Head and neck squamous cell carcinoma (HNSCC) remains a morbid disease with poor prognosis and treatment that typically leaves patients with permanent damage to critical functions such as eating and talking. Currently only three targeted therapies are FDA approved for use in HNSCC, two of which are recently approved immunotherapies. In this work, we identify biological pathways involved with this disease that could potentially be targeted by current FDA approved cancer drugs and thereby expand the pool of potential therapies for use in HNSCC treatment. We analyzed 508 HNSCC patients with sequencing information from the Genomic Data Commons (GDC) database and assessed which biological pathways were significantly enriched for somatic mutations or copy number alterations. We then further classified pathways as either "light" or "dark" to the current reach of FDA-approved cancer drugs using the Cancer Targetome, a compendium of drug-target information. Light pathways are statistically enriched with somatic mutations (or copy number alterations) and contain one or more targets of current FDA-approved cancer drugs, while dark pathways are enriched with somatic mutations (or copy number alterations) but not currently targeted by FDA-approved cancer drugs. Our analyses indicated that approximately 35-38% of disease-specific pathways are in scope for repurposing of current cancer drugs. We further assess light and dark pathways for subgroups of patient tumor samples according to HPV status. The framework of light and dark pathways for HNSCC-enriched biological pathways allows us to better prioritize targeted therapies for further research in HNSCC based on the HNSCC genetic landscape and FDA-approved cancer drug information. We also highlight the importance in the identification of sub-pathways where targeting and cross targeting of other pathways may be most beneficial to predict positive or negative synergy with potential clinical significance. This framework is ideal for precision drug panel development, as well as identification of highly aberrant, untargeted candidates for future drug development.

Dataset Information

Phosphoproteomic analysis of signaling pathways in head and neck squamous cell carcinoma patient samples.

Publications

Phosphoproteomic analysis of signaling pathways in head and neck squamous cell carcinoma patient samples.

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