652 EPAC-mTORC1 signaling regulates proliferation of primary melanoma cells and loss of dependence on EPAC signaling correlates with melanoma progression

Exchange Proteins directly Activated by cAMP (EPACs) belong to a family of RAP guanine nucleotide exchange factors (RAPGEF). EPAC1/2 (RAPGEF3/4) activate RAP1 and the alternative signaling pathway. We previously showed that differential growth response primary metastatic melanoma cells is mediated EPAC. However, mechanisms responsible for this EPAC are not understood. In study, we show pharmacological inhibition or siRNA-mediated knockdown selectively inhibits survival downregulation cell cycle proteins inhibiting progression independent ERK1/2 phosphorylation. results in upregulation AKT phosphorylation but mTORC1 activity its downstream effectors. also regulates both glycolysis oxidative phosphorylation, production mitochondrial reactive oxygen species, preferentially cells. Employing series genetically matched lymph node (LNM) cells, distant organ (MM) LNM MM become progressively less responsive refractory suggesting loss dependency on correlates with progression. Analysis TCGA dataset lower RAPGEF3, RAPGEF4 mRNA expression tumor predictor better disease-free patients diagnosed facilitates useful prognostic marker. These data highlight as potential target prevention