Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers

Abstract

Activation of the PI3K and epidermal growth factor receptor (EGFR) pathway is able to drive oncogenesis in multiple human cancers, including head and neck squamous cell carcinoma. Targeted agents such as cetuximab and erlotinib are currently used in patients with head and neck squamous cell carcinoma, but, in this disease, the genomic alterations that cause pathway activation and determine response to pharmacologic inhibition remain ill-defined. Here, we present a detailed dissection of the EGFR/PI3K pathway, composed of sequencing of the core pathway components, and high-resolution genomic copy number assessment. Mutations were found in PIK3CA (6%), but no point mutations were observed in other pathway genes such as PTEN and EGFR . In contrast, we observed frequent copy number alterations of genes in the pathway, including PIK3CA , EGFR , protein tyrosine phosphatase receptor S ( PTPRS ), and RICTOR . In total, activating genetic pathway alterations were identified in 74% of head and neck tumors. Importantly, intragenic microdeletions of the EGFR phosphatase PTPRS were frequent (26%), identifying this gene as a target of 19p13 loss. PTPRS loss promoted EGFR/PI3K pathway activation, modulated resistance to EGFR inhibition, and strongly determined survival in lung cancer patients with activating EGFR mutations. These findings have important implications for our understanding of head and neck cancer tumorigenesis and for the use of targeted agents for this malignancy.

Protein tyrosine phosphatase receptor S acts as a metastatic suppressor in hepatocellular carcinoma by control of epithermal growth factor receptor–induced epithelial‐mesenchymal transition

“…These findings were in line with evidence that EGFR participated in the PTPRS-regulated PI3K/protein kinase B-signaling pathway. 18 However, alterations of PTPRS expression resulted in phosphorylation changes of multiple RTKs, as revealed by PTK array, suggesting that other potential direct/ indirect substrates of PTPRS need further investigation.…”

“…In line with our findings, loss of PTPRS had been reported in head and neck carcinoma and closely related to chemotherapy resistance. 18 However, PTPRS expression pattern, derived from TCGA database (Supporting Fig. 1), in several types of human cancer indicated that a tumorspecific investigation on the role of PTPRS was required.…”

“…17 Recently, involvement of PTPRS in cancer came from evidence in head and neck squamous-cell carcinoma, where frequent deletion (26%) of PTPRS was detected. 18 Meanwhile, whole-genome sequencing approaches have uncovered several mutations in PTPRS, such as V224M in colorectal cancer, 19 P141S in malignant melanoma, 20 and A1384T in cholangiocarcinoma. 21 Although most of these mutations are located in the phosphatase region, which might lead to loss of phosphatase activity, the exact biological impact and molecular basis remain unclear.…”

A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

“…First, PTPR proteins are mutated with a 30% frequency across 15 types of solid tumors (29). Second, PTPRS is specifically microdeleted in 26% of head and neck cancer patients (34). Third, PTPRS function is modulated by shedding (35) suggesting that its tumor suppressor activity could be abrogated by ADAM17-mediated shedding.…”

Bioinformatics in otolaryngology research. Part two: other high-throughput platforms in genomics and epigenetics

“…2 In this study, which acts as an example of the application of comparative genome hybridisation arrays in head and neck cancer, several alterations in the EGFR/PI3K pathway were identified, including novel microdeletions in the PTPRS gene.…”