Morgan Black1, Farhad Ghasemi2, Ren X Sun3, William Stecho4, Alessandro Datti5, Jalna Meens6, Nicole Pinto1, Kara M Ruicci1, M Imran Khan2, Myung Woul Han2, Mushfiq Shaikh2, John Yoo1, Kevin Fung1, Danielle MacNeil1, David A Palma7, Eric Winquist7, Christopher J Howlett4, Joe S Mymryk8, Laurie Ailles9, Paul C Boutros10, John W Barrett1, Anthony C Nichols11. 1. Department of Otolaryngology, London Health Sciences Centre, London, Ontario, Canada; Department of Oncology, London Health Sciences Centre, London, Ontario, Canada. 2. Department of Otolaryngology, London Health Sciences Centre, London, Ontario, Canada. 3. Informatics & Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. 4. Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, Ontario, Canada. 5. Department of Agricultural, Food, and Environmental Sciences, University of Perugia, Perugia, Italy. Electronic address: alessandro.datti@unipg.it. 6. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. 7. Department of Oncology, London Health Sciences Centre, London, Ontario, Canada. 8. Department of Otolaryngology, London Health Sciences Centre, London, Ontario, Canada; Department of Oncology, London Health Sciences Centre, London, Ontario, Canada; Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada. 9. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. 10. Informatics & Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. 11. Department of Otolaryngology, London Health Sciences Centre, London, Ontario, Canada; Department of Oncology, London Health Sciences Centre, London, Ontario, Canada. Electronic address: anthony.nichols@lhsc.on.ca.
Abstract
OBJECTIVES: Spleen tyrosine kinase (SYK) is a promoter of cell survival in a variety of cell types, including normal and cancerous epithelial cells. We hypothesized that SYK would an important therapeutic target to inhibit for the treatment of HNSCC. MATERIALS AND METHODS: SYK protein abundance in patient tumours was evaluated. SYK protein and mRNA abundance was used to examine patient survival and human papillomavirus (HPV) status. Small-interfering RNAs and gene editing with CRISPR/Cas9 were used to evaluate SYK expression on proliferation in HNSCC cell lines. The potency of SYK inhibitor ER27319 maleate on cellular proliferation was tested using a panel of 28 HNSCC cell lines and in vivo in HNSCC patient-derived xenograft (PDX) models. RESULTS: Moderate to high protein expression of SYK was observed in 24% of patient tumors and high SYK expression was exclusively observed in HPV-positive samples (p < 0.001). SYK inhibition with RNA interference, gene editing or a SYK inhibitor (ER27319) decreased cell proliferation and migration. Treatment of PDXs with ER27319 maleate was observed to reduce tumour burden in vivo in two of three models. CONCLUSIONS: HPV-positive HNSCC harbours high SYK protein levels. We demonstrate that proliferation, migration and overall burden of these tumours can be reduced by genetic or pharmacologic inhibition of SYK. Taken together, these data establish SYK as a therapeutic target for HNSCC.
OBJECTIVES:Spleen tyrosine kinase (SYK) is a promoter of cell survival in a variety of cell types, including normal and cancerous epithelial cells. We hypothesized that SYK would an important therapeutic target to inhibit for the treatment of HNSCC. MATERIALS AND METHODS:SYK protein abundance in patienttumours was evaluated. SYK protein and mRNA abundance was used to examine patient survival and human papillomavirus (HPV) status. Small-interfering RNAs and gene editing with CRISPR/Cas9 were used to evaluate SYK expression on proliferation in HNSCC cell lines. The potency of SYK inhibitor ER27319 maleate on cellular proliferation was tested using a panel of 28 HNSCC cell lines and in vivo in HNSCC patient-derived xenograft (PDX) models. RESULTS: Moderate to high protein expression of SYK was observed in 24% of patienttumors and high SYK expression was exclusively observed in HPV-positive samples (p < 0.001). SYK inhibition with RNA interference, gene editing or a SYK inhibitor (ER27319) decreased cell proliferation and migration. Treatment of PDXs with ER27319 maleate was observed to reduce tumour burden in vivo in two of three models. CONCLUSIONS:HPV-positive HNSCC harbours high SYK protein levels. We demonstrate that proliferation, migration and overall burden of these tumours can be reduced by genetic or pharmacologic inhibition of SYK. Taken together, these data establish SYK as a therapeutic target for HNSCC.