n-(3-4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2-3-dihydroxypropyl)cyclopropane-1-sulfonamide and Pseudomyxoma-Peritonei

Excessive accumulation of mucin 2 (MUC2) protein (a gel-forming secreted mucin) within the peritoneal cavity is the major cause of morbidity and mortality in pseudomyxoma peritonei (PMP), a unique mucinous malignancy of the appendix. Mitogen-activated protein kinase (MAPK) signaling pathway is upregulated in PMP and has been shown to modulate MUC2 promoter activity. We hypothesized that targeted inhibition of the MAPK pathway would be a novel, effective, and safe therapeutic strategy to reduce MUC2 production and mucinous tumor growth. We tested RDEA119, a specific MEK1/2 (MAPK extracellular signal-regulated kinase [ERK] kinase) inhibitor, in MUC2-secreting LS174T cells, human PMP explant tissue, and in a unique intraperitoneal murine xenograft model of PMP. RDEA119 reduced ERK1/2 phosphorylation and inhibited MUC2 messenger RNA and protein expression in vitro. In the xenograft model, chronic oral therapy with RDEA119 inhibited mucinous tumor growth in an MAPK pathway-dependent manner and this translated into a significant improvement in survival. RDEA119 downregulated phosphorylated ERK1/2 and nuclear factor κB p65 protein signaling and reduced activating protein 1 (AP1) transcription factor binding to the MUC2 promoter in LS174T cells. This study provides a preclinical rationale for the use of MEK inhibitors to treat patients with PMP.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Diphenylamine; Humans; MAP Kinase Signaling System; Mice, Nude; Mitogen-Activated Protein Kinases; Mucin-2; Neoplasms, Cystic, Mucinous, and Serous; NF-kappa B; Peritoneal Neoplasms; Promoter Regions, Genetic; Protein Kinase Inhibitors; Pseudomyxoma Peritonei; Sulfonamides; Survival Analysis; Transcription Factor AP-1; Xenograft Model Antitumor Assays