pd-0325901 and Carcinoma--Pancreatic-Ductal

Constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway is essential for tumorigenesis of pancreatic ductal adenocarcinoma (PDAC). To date, however, almost all clinical trials of inhibitor targeting this pathway have failed to improve the outcome of patients with PDAC. We found that implanted MIA Paca2, a human PDAC cell line sensitive to a MAPK inhibitor, PD0325901, became refractory within a week after treatment. By comparing the expression profiles of MIA Paca2 before and after acquisition of the refractoriness to PD0325901, we identified clusterin (CLU) as a candidate gene involved. CLU was shown to be induced immediately after treatment with PD0325901 or expressed primarily in more than half of PDAC cell lines, enhancing cell viability by escaping from apoptosis. A combination of PD0325901 and CLU downregulation was found to synergistically or additively reduce the proliferation of PDAC cells. In surgically resected PDAC tissues, overexpression of CLU in cancer cells was observed immunohistochemically in approximately half of the cases studied. Collectively, our findings highlight the mechanisms responsible for the rapid refractory response to MEK inhibitor in PDAC cells, suggesting a novel therapeutic strategy that could be applicable to patients with PDAC using inhibitor targeting the MAPK signaling pathway and CLU.

Topics: Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Clusterin; Humans; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Pancreatic Neoplasms; Protein Kinase Inhibitors

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bcl-2-Like Protein 11; Benzamides; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Survival; Diphenylamine; Drug Screening Assays, Antitumor; Humans; MAP Kinase Signaling System; Morpholines; Mutation; Myeloid Cell Leukemia Sequence 1 Protein; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); RNA, Small Interfering; TOR Serine-Threonine Kinases; Triazines