Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with an increasing incidence.,The understanding of the molecular carcinogenesis of MCC is limited.,Here, we scrutinized the PI3K/AKT pathway, one of the major pathways activated in human cancer, in MCC.,Immunohistochemical analysis of 41 tumor tissues and 9 MCC cell lines revealed high levels of AKT phosphorylation at threonine 308 in 88% of samples.,Notably, the AKT phosphorylation was not correlated with the presence or absence of the Merkel cell polyoma virus (MCV).,Accordingly, knock-down of the large and small T antigen by shRNA in MCV positive MCC cells did not affect phosphorylation of AKT.,We also analyzed 46 MCC samples for activating PIK3CA and AKT1 mutations.,Oncogenic PIK3CA mutations were found in 2/46 (4%) MCCs whereas mutations in exon 4 of AKT1 were absent.,MCC cell lines demonstrated a high sensitivity towards the PI3K inhibitor LY-294002.,This finding together with our observation that the PI3K/AKT pathway is activated in the majority of human MCCs identifies PI3K/AKT as a potential new therapeutic target for MCC patients.
Epigenetic proteins are intently pursued targets in ligand discovery.,To date, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic “writers” and “erasers”.,Potent inhibitors of histone binding modules have not yet been described.,Here we report a cell-permeable small molecule (JQ1) which binds competitively to acetyl-lysine recognition motifs, or bromodomains.,High potency and specificity toward a subset of human bromodomains is explained by co-crystal structures with BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity.,Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma.,Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific anti-proliferative effects in BRD4-dependent cell lines and patient-derived xenograft models.,These data establish proof of concept for targeting protein-protein interactions of epigenetic “readers” and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.