2015-08-12

Background Protein tyrosine phosphatase receptor type D (PTPRD) is a putative tumor suppressor in several cancers including head and neck squamous cell carcinoma (HNSCC). STAT3 is a frequently hyperactivated oncogene in HNSCC. As STAT3 is a direct substrate of PTPRD, we sought to determine the genetic or epigenetic alterations of PTPRD that contribute to overactive STAT3 in HNSCC. Methods We analyzed data from The Cancer Genome Atlas (TCGA) and our previous whole-exome sequencing study and summarized the mutation, methylation, and copy number status of PTPRD in HNSCC and other cancers. In vitro studies involved standard transfection and MTT protocols, as well as methylation-specific PCR. Results Our findings indicate that PTPRD mutation, rather than methylation or copy number alteration, is the primary mechanism by which PTPRD function is lost in HNSCC. We demonstrate that overexpression of wild-type PTPRD in HNSCC cells significantly inhibits growth and STAT3 activation while PTPRD mutants do not, suggesting that mutation may lead to loss of function and subsequent hyper-phosphorylation of PTPRD substrates, especially STAT3. Importantly, we determined that HNSCC cells harboring an endogenous PTPRD mutation are more sensitive to STAT3 blockade than PTPRD wild-type cells. We additionally found that PTPRD mRNA expression does not correlate with pSTAT3 expression, suggesting that alterations that manifest through altered mRNA expression, including hypermethylation and gene copy number alterations, do not significantly contribute to STAT3 overactivation in HNSCC. Conclusion PTPRD mutation, but not methylation or copy number loss, may serve as a predictive biomarker of sensitivity to STAT3 inhibitors in HNSCC.

Peyser, ND, Du, Y, Li, H, Lui, V, Xiao, X, Chan, TA, Grandis, JR. (2015). Data from: Loss-of-Function PTPRD Mutations Lead to Increased STAT3 Activation and Sensitivity to STAT3 Inhibition in Head and Neck Cancer. [Data File]. Genomic and proteomic data are available from The Cancer Genome Atlas (https://tcga-data.nci.nih.gov/tcga/dataAccessMatrix.htm) and The Cancer Proteome Atlas (http://app1.bioinformatics.mdanderson.org/tcpa/_design/basic/index.html).
Click on “Linked Publications” to access the publication and access supporting information on figshare at https://figshare.com/articles/Loss_of_Function_PTPRD_Mutations_Lead_to_Increased_STAT3_Activation_and_Sensitivity_to_STAT3_Inhibition_in_Head_and_Neck_Cancer/1509783

PTPRD mRNA expression

STAT 3 blockade

STAT 3

STAT 3 inhibitors

pSTAT 3 expression

PTPRD mutation

STAT 3. Importantly

STAT 3 activation

HNSCC cells

STAT 3 overactivation

Neck Cancer BackgroundProtein tyrosine phosphatase receptor type D

TCGA

STAT 3 Inhibition

Gene Copy Number Alterations

Cancer Genome Atlas

mtt

copy number alteration

copy number loss

copy number status