Novel targets to treat Merkel Cell Carcinomas Mechanistic and biological activities linked to the activity of EGFR, FGFR and IGFR receptors
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Merkel Cell Carcinoma (MCC) is a relatively rare neuroendocrine tumor of the skin with an increasing incidence. It is an aggressive type of cancer with a high mortality rate (about 40%), exceeding that of cutaneous melanoma. MCCs are divided into two different subtypes: A) MCPyV-positive, with low mutational index, and B) MCPyV-negative, with high mutational index and U.V. signatures. There is little knowledge about the driving mechanisms of MCC as reflected by the lack of specific targeted therapy. Interestingly, immunotherapy using immune checkpoints inhibitors can benefit up to 50% of the total number of cases independently of their etiology. In an effort to characterize MCC tumors, recent studies using Next Generation Sequencing approaches, have uncover important mechanisms driving this disease. In this regard and but to name a few, alterations in TP53 and RB, deregulated NOTCH and PI3K signaling. Activated P-CREB has been identified as an independent factor for adverse prognosis in MCCs from both etiologies. Alongside CREB, we have detected members of the cell surface receptors with intrinsic tyrosine kinase activity (RTKs hereon) frequently mutated in MCCs. To gain deeper insight into the role of RTK and CREB in the biology of MCC cells, we decided to study the role of specific RTKs in promoting CREB phosphorylation and the biological effects that specific RTK inhibitors provoke in a panel of MCPyV+ and MCPyV- cells. Our data shows that members of the EGFR, FGFR can promote the activation of CREB and ERK in MCC cells. In addition, we tested four RTK inhibitors (BGJ-398, BMS-754807, Dacomotinib-PF299 and Sorafenib Tosylato) and show that they can inhibit MCC cell proliferation in a concentration dependent manner and increase apoptosis. Thus our results show that specific RTKs and its downstream signaling can participate in malignant MCC biological activities and may serve as potential targets for therapy in MCC.