Loss-of-Function PTPRD Mutations Lead to Increased STAT3 Activation and Sensitivity to STAT3 Inhibition in Head and Neck Cancer.
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.


CONCLUSIONS
PTPRD mutation, but not methylation or copy number loss, may serve as a predictive biomarker of sensitivity to STAT3 inhibitors in HNSCC.
Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America, 15213; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America, 15213.
Noah D
ND
Peyser
Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America, 15213; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America, 15213; School of Medicine, Tsinghua University, Beijing, China, 100084.
Yu
Y
Du
Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America, 15213.
Hua
H
Li
Pharmacogenomics and Precision Therapeutics Laboratory, Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR, China; Department of Biochemistry, The University of Hong Kong, Hong Kong SAR, China.
Vivian
V
Lui
Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America, 15213.
Xiao
X
Xiao
Human Oncology and Pathogenesis Program and Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, United States of America, 10065.
Timothy A
TA
Chan
Department of Otolaryngology, University of California San Francisco, San Francisco, CA, United States of America, 94143.
Jennifer R
JR
Grandis
D002460:Cell Line; D019175:DNA Methylation / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000235:genetics
D050796:STAT3 Transcription Factor; C090899:PTPRD protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2