Biological and transcriptional effects of RTKs inhibition ; EGFR, FGFR and IGFR as new therapeutic targets for MCC

Abstract

ABSTRACT : Merkel Cell Carcinoma is a rare neuroendocrine tumor of the skin with an increasing incidence. It is a very aggressive type of cancer with a high mortality rate (30% of its patients). There are two main etiologies, MCPyV + tumors, characterized by the presence of the integrated Merkel Polyoma virus (MCPyV) and low mutational index, and MCPyV- tumors displaying high mutational burdens with a typical UV mutational signature, caused by exposure to UV radiation. Today, treatments for MCC are based on surgical excision along with adjuvant radiation therapy or chemotherapy, which shopw only limited effects. There is a current lack of knowledge about the driver mechanisms of MCC carcinogenesis, which is reflected in the lack of biomarkers for diagnosis and targeted therapy. Some recent studies have focused on characterizing MCC tumors to discover the mechanisms that drive this disease. As part of these initiatives, activated CREB has been shown as an independent factor of mortality caused by MCC. Continuing with the mechanistic characterization of MCC tumors, numerous mutations in receptors with tyrosine kinase activity (RTK) have been detected in MCC tumors. Therefore, to study the role of RTKs-dependent signaling in a CREB context, we decided to carry out a study on the different biochemical (CREB activation) and biological effects (proliferation and apoptosis) caused by different RTK inhibitors in a collection of MCC cell lines (MCPyV- and MCPyV +). In this regard, we have taken advantage of the compounds M666-15 (a selective CREB inhibitor, CREBi), dacomitinib (anEGFRi), BGJ 398 (FGFRi), and BMS-754807 (which inhibits IGF-1R/InsR and TrkA/B). These were highly effective at inhibiting MCC cell proliferation. Moreover, dacomitinib, BGJ-398, and BMS754807 induced apoptosis in MCC cell lines, as well as reducing binding of CREB and P-CREB to specific DNA elements. Therefore, our study shows that deregulated RTK activities towards CREB activation can be crucial in promoting MCC carcinogenesis and therefore constitute and important mechanisms of MCC tumorugenesis that we can target wich specific inhibitors.