crizotinib and Peritoneal-Neoplasms

Peritoneal carcinomatosis (PC) is progression of the primary cancer to the peritoneum that is seen in only 1.2% of patients with lung cancer. It is associated with poor prognosis especially if present at the time of initial cancer diagnosis. The predisposing factors for peritoneal spread are not yet well understood. It has been suggested that the oncogene status of the tumour can influence the patterns of metastatic spread. There is not enough data about the role of c-ROS oncogene 1 (ROS1) mutation in the development of PC in non-small cell lung cancer. Here, we describe a case of a 56-year-old man who presented with new-onset ascites and was found to have PC. He was diagnosed with ROS1-rearranged lung adenocarcinoma. No obvious primary tumour was identified. Patient responded well to targeted therapy with crizotinib and remained 6 months free of disease progression.

Topics: Adenocarcinoma of Lung; Crizotinib; Diagnosis, Differential; Gene Rearrangement; Humans; Lung Neoplasms; Male; Middle Aged; Peritoneal Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins

Peritoneal dissemination is a frequent occurrence in pancreatic cancer, which is associated with a poor prognosis. MET is associated with the progression of pancreatic cancer; therefore, we evaluated the effect of a MET inhibitor, crizotinib, on peritoneal dissemination of pancreatic cancer. Crizotinib inhibited the growth of 8 pancreatic cancer cell lines with the IC50 ranging from 1.4 to 4.3 µM. Invasion of the pancreatic cancer cell line Suit-2, was suppressed in vitro at a concentration of 1.0 µM, which is sufficient for the inhibition of MET phosphorylation. This effect on cell invasion was also recapitulated by the reduction of MET expression in Suit-2 with siRNA. Crizotinib also inhibited RhoA activation in addition to MET phosphorylation. We further evaluated the effect of crizotinib on peritoneal dissemination of pancreatic cancer in vivo. Crizotinib reduced tumor burden and ascites accumulation due to development of peritoneal dissemination after inoculation of Suit-2. Taken together, crizotinib may be a potent drug for treating peritoneal dissemination of pancreatic cancer by inhibiting cancer cell proliferation and invasion, at least in part through the suppression of HGF/MET signaling and RhoA activation.

Topics: Animals; Apoptosis; Biomarkers, Tumor; Cell Proliferation; Crizotinib; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Pancreatic Neoplasms; Peritoneal Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Signal Transduction; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Scirrhous gastric cancer is associated with abundant stroma and frequently develops into peritoneal carcinomatosis with malignant ascites. Although malignant ascites is among the most deadly diseases worldwide, its molecular pathogenesis is poorly understood. We investigated the role of hepatocyte growth factor (HGF) in the production of peritoneal carcinomatosis with malignant ascites. We examined three scirrhous and three non-scirrhous human gastric cancer cell lines for the production of peritoneal carcinomatosis in vivo and responses to HGF in vitro. Furthermore, clinical scirrhous gastric cancer specimens were examined for HGF production. Among the six cell lines examined, only two scirrhous cell lines (NUGC4 and GCIY) produced peritoneal carcinomatosis with massive ascites after intraperitoneal injection in nude mice. Their proliferation was stimulated by exogenous HGF in vitro. On the other hand, a non-scirrhous cell line, MKN45, with MET amplification generated peritoneal tumors but not ascites. MET tyrosine kinase inhibitors, crizotinib and TAS-115, inhibited HGF-stimulated proliferation of NUGC4 and GCIY as well as constitutive proliferation of MKN45. Furthermore, crizotinib and TAS-115 prolonged the survival of mice bearing established tumors by NUGC4 or MKN45. In clinical specimens, HGF was markedly produced by stromal fibroblasts. Malignant ascitic fluids from patients with peritoneal carcinomatosis contained high levels of HGF. Our results strongly suggest that paracrine HGF-induced activation of MET-mediated signaling pathways plays an important role in the pathogenesis of peritoneal carcinomatosis in scirrhous gastric cancer. Thus, MET signaling pathway may be a potential therapeutic target for peritoneal carcinomatosis of gastric cancer, even without MET amplification.

Topics: Adenocarcinoma, Scirrhous; Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Crizotinib; Fibroblasts; Hepatocyte Growth Factor; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Peritoneal Neoplasms; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Signal Transduction; Stomach Neoplasms; Stromal Cells; Xenograft Model Antitumor Assays