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Retinoblastoma is a malignant tumour of the retina which most often occurs in children. Earlier studies on retinoblastoma have concentrated on the identification of key players in the disease and have not provided information on activated/inhibited signalling pathways. The dysregulation of protein phosphorylation in cancer provides clues about the affected signalling cascades in cancer. Phosphoproteomics is an ideal tool for the study of phosphorylation changes in proteins. Hence, global phosphoproteomics of retinoblastoma (RB) was carried out to identify signalling events associated with this cancer. Over 350 proteins showed differential phosphorylation in RB compared to control retina. Our study identified stress response proteins to be hyperphosphorylated in RB which included H2A histone family member X (H2AFX) and sirtuin 1. In particular, Ser140 of H2AFX also known as gamma-H2AX was found to be hyperphosphorylated in retinoblastoma, which indicated the activation of DNA damage response pathways. We also observed the activation of anti-apoptosis in retinoblastoma compared to control. These observations showed the activation of survival pathways in retinoblastoma. The identification of hyperphosphorylated protein kinases including Bromodomain containing 4 (BRD4), Lysine deficient protein kinase 1 (WNK1), and Cyclin-dependent kinase 1 (CDK1) in RB opens new avenues for the treatment of RB. These kinases can be considered as probable therapeutic targets for RB, as small-molecule inhibitors for some of these kinases are already in clinical trials for the treatment other cancers.

// Hanna Ning 1,* , Hiroshi Mitsui 1,* , Claire Q.F. Wang 1 , Mayte Suarez-Farinas 1,2 , Juana Gonzalez 1,2 , Kejal R. Shah 3 , Jie Chen 4 , Israel Coats 1 , Diane Felsen 4 , John A. Carucci 5 , and James G. Krueger 1 1 Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY 2 Center for Clinical and Translational Science, The Rockefeller University, New York, New York, USA 3 Texas Dermatology Associates, Baylor University Medical Center, Dallas, TX USA 4 Institute for Pediatric Urology, Department of Urology, Weill Cornell Medical College, New York, NY 5 Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center, New York, NY * These two authors contributed equally to this manuscript. Correspondence: James G. Krueger, email: // Keywords : Basal cell carcinoma, oncogenic kinases, cancer, therapy Received : September 1, 2013 Accepted : September 30, 2013 Published : October 2, 2013 Abstract The pathogenesis of BCC is associated with sonic hedgehog (SHH) signaling. Vismodegib, a smoothened inhibitor that targets this pathway, is now in clinical use for advanced BCC patients, but its efficacy is limited. Therefore, new therapeutic options for this cancer are required. We studied gene expression profiling of BCC tumour tissues coupled with laser capture microdissection to identify tumour specific receptor tyrosine kinase expression that can be targeted by small molecule inhibitors. We found a >250 fold increase (FDR