Our lab showed that HDACi Belinostat induced the expression of epigenetically silent TGFb RII and therefore restored TGFb signaling-mediated cell growth inhibition in Smad4 wild type Ruxolitinib pancreatic cancer cells,. Ron is highly expressed in Smad4 mutant pancreatic cancer cells. Wild type Smad4 expression was reported to suppress Ron expression. Knockdown of Smad4 or inhibition of TGFb signaling resulted in induction of Ron expression. The studies here show that HDACi PS and TSA downregulated Ron and its downstream signaling in pancreatic cancer cells. Ron KD or Ron mAb sensitized pancreatic cancer cells to PS. Oral PS has been used in phase II clinical trial in adult patients with refractory/ relapsed Hodgkin��s lymphoma and phase I trial for advanced solid tumor. Our studies have explored a possible mechanism underlying PS treatment of pancreatic cancer and provided important evidence for the potential of a rational combination treatment for Ron-expressing pancreatic cancer cells. This study identified a potential novel therapeutic approach in pancreatic cancer using a combination strategy through exploiting both genetic and epigenetic features. Pancreatic cancer is one of the most challenging problems in cancer therapy. Current chemotherapy by gemcitabine has a very low response rate and drug resistance develops rapidly resulting in treatment failure. Thus, new therapeutic strategies are urgently needed. Ron has been recently reported to be highly expressed in pancreatic cancer cells and patient samples. Stimulation with MSP activates Ron and its downstream signaling, including PI3K/ Akt and MAPK and promotes cell migration and invasion. However, Ron activation had no effect on proliferation in pancreatic cancer cells. Knockdown of Ron has shown increased susceptibility to apoptosis of colon cancer cells to growth factor deprivation stress through mutant p110a activation. However, pancreatic cancer cells do not contain p110a mutations. Ron KD had no effect on cell proliferation and apoptosis as assessed by MTT, PARP and caspase 9 cleavages in vitro in pancreatic cancer cells. Our studies here showed that IMC-RON8 downmodulated Ron expression, which was consistent with previous studies that mouse Reversine anti-Ron mAbs Zt/g4, Zt/f2 and Zt/c9 reduced Ron expression in colon cancer cells. Human mAb IMC-41A10 efficiently reduced MSP-mediated Ron activation and its downstream PI3K/Akt and MAPK activation. MAPK signaling reduction by IMC41A10 was evidenced by pERK reduction in all the cancer cell lines chosen. However, the effect of IMC41A10 on pAkt is not consistent in all the cell lines. For example, IMC41A10 had strong impact on the reduction of Akt activation in HT29, Du-145 and AGS, whereas IMC-41A10 did not change pAkt in other cells including the pancreatic cancer cell line BxPC3. IMC-RON8, another fully human anti-Ron mAb, displayed antitumor activity against human colon, lung and pancreatic xenografts in nude mice. Our studies here demonstrated that IMC-RON8 effectively inhibited Ron phosphorylation in CFPAC-1 cells, as well as downstream pMAPK and pAkt activation in all the pancreatic cancer cell lines we examined including BxPC3.