Abstract 4260: PTPRT mutation induces STAT3 activation in HNSCC preclinical models.
Authors: Lui Vivian , Peyser Noah , Shing NG Patrick Kwok , Sen Malabika , Li Hua , Zeng Yan , Joyce Sonali , Wang Zhenghe John , Hammerman Peter , Mills Gordon , Grandis Jennifer R. 
Published: August 2014

Abstract
Purpose: Head and neck squamous cell carcinoma (HNSCC) is an invasive malignancy with more than 40,000 cases diagnosed annually in the United States. Increased activation of signal transducer and activator of transcription 3 (STAT3) has been implicated in HNSCC tumorigenesis, although the mechanisms underlying aberrant STAT3 signaling are not fully elucidated. Activation of kinases upstream of STAT3 signaling, such as the epidermal growth factor receptor (EGFR), Janus kinase (JAK), and Src kinase, likely contribute, but downstream inactivators of STAT3 signaling, especially protein tyrosine phosphatases, remain incompletely understood. We recently elucidated the mutational profile of 74 HNSCC tumors and detected mutations in the receptor-like protein tyrosine phosphatase (PTPR) family in nearly one third of samples analyzed. Notably, known activating mutations of upstream kinases, including EGFR, JAK, and Src kinase, were not found. These findings were confirmed in an expanded cohort of 279 HNSCC tumors. High frequencies of PTPRT mutations have also been reported in other human cancers including colorectal cancer, lung carcinomas, and glioblastomas. Of these genes, PTPRT was mutated most frequently, with a total of 20 novel non-synonymous mutations detected in HNSCC tumors. Importantly, wild-type PTPRT was recently reported by others directly dephosphorylate STAT3. We therefore hypothesize that mutational inactivation of PTPRT contributes to HNSCC tumorigenesis via hyperphosphorylation of STAT3.
Experimental Design: We assessed the contribution of mutant PTPRT to STAT3 phosphorylation and cell proliferation in preclinical HNSCC models. Cell lines expressing wild-type or mutant PTPRT either transiently or stably by retroviral infection were generated. Levels of pSTAT3 were determined by Western blot and cell proliferation determined by trypan blue exclusion assay.
Results: PTPRT was shown in pre-clinical models to regulate STAT3 phosphorylation. Cells expressing HNSCC tumor-derived mutants of PTPRT exhibited elevated levels of pSTAT3 and increased cell proliferation.
Conclusion: Our results indicate that STAT3 is regulated by PTPRT in HNSCC and that mutation of PTPRT leads to an increase in STAT3 activation and cell proliferation. These findings suggest that PTPRT mutations may contribute to HNSCC tumor growth and progression via loss of function and subsequent hyperphosphorylation of STAT3. In the future, mutation of PTPRT may serve as a biomarker for a subset of tumors that are sensitive to treatment with STAT3 inhibitors.
Citation Format: Vivian Lui, Noah Peyser, Patrick Kwok Shing NG, Malabika Sen, Hua Li, Yan Zeng, Sonali Joyce, Zhenghe John Wang, Peter Hammerman, Gordon Mills, Jennifer R. Grandis. PTPRT mutation induces STAT3 activation in HNSCC preclinical models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4260. doi:10.1158/1538-7445.AM2013-4260