ph-797804 and Adenocarcinoma

Colorectal cancer is a major health problem and the second cause of cancer related death in western countries. Signaling pathways that control tissue homeostasis are often deregulated during tumorigenesis and contribute to tumor development. Studies in mouse models have shown that the p38 MAPK pathway regulates homeostasis in colon epithelial cells but also plays an important role in colon tumor maintenance. In this study, we have investigated the role of p38 MAPK signaling in patient-derived xenografts (PDXs) from three different human colon tumors representing clinical heterogeneity and that recapitulate the human tumor conditions both at histological and molecular levels. We have found that PH797804, a chemical inhibitor of p38 MAPK, reduces tumor growth of the three PDXs, which correlates with impaired colon tumor cell proliferation and survival. The inhibition of p38 MAPK in PDXs results in downregulation of the IL-6/STAT3 signaling pathway, which is a key regulator of colon tumorigenesis. Our results show the importance of p38 MAPK in human colon tumor growth using a preclinical model, and support that inhibition of p38 MAPK signaling may have therapeutic interest for colon cancer treatment.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Benzamides; Carcinoma, Neuroendocrine; Cell Differentiation; Colonic Neoplasms; Cytokines; Genes, ras; Humans; Liver Neoplasms; MAP Kinase Signaling System; Mice; Mice, Nude; Mutation; Neoplasm Proteins; Neoplasm Staging; p38 Mitogen-Activated Protein Kinases; Protein Kinase Inhibitors; Pyridones; Tumor Cells, Cultured; Xenograft Model Antitumor Assays