title: Dasatinib modulates sensitivity to pemetrexed in malignant pleural mesothelioma cell lines.
abstract: BACKGROUND
  Thymidylate synthase (TS), one of the key enzymes for thymidine synthesis, is a target of pemetrexed (PEM), a key agent for the systemic therapy of malignant pleural mesothelioma (MPM) and its overexpression has been correlated to PEM-resistance. In MPM, experimental data report activation of the c-SRC tyrosine kinase suggesting it as a potential target to be further investigated.
  
  
  RESULTS
  MPM cell lines showed different sensitivity, being MSTO the most and REN the least sensitive to PEM. REN cells showed high levels of both TS and SRC: dasatinib inhibited SRC activation and suppressed TS protein expression, starting from 100 nM dose, blocking the PEM-induced up regulation of TS protein levels. Dasatinib treatment impaired cells migration, and both sequential and co-administration with PEM significantly increased apoptosis. Dasatinib pretreatment improved sensitivity to PEM, downregulated TS promoter activity and, in association with PEM, modulated the downstream PI3K-Akt-mTOR signaling. Cell lines and Methods: In three MPM cell lines (MPP89, REN and MSTO), the effects of c-SRC inhibition, in correlation with TS expression and PEM sensitivity, were evaluated. PEM and dasatinib, a SRC inhibitor, were administered as single agents, in combination or sequentially. Cell viability, apoptosis and migration, as well as TS expression and SRC activation have been assessed.
  
  
  CONCLUSIONS
  These data indicate that dasatinib sensitizes mesothelioma cells to PEM through TS down-regulation.
authors.affiliation: Department of Oncology, University of Torino, San Luigi Hospital, Orbassano, Torino, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Monica
authors.affiliation: Department of Oncology, University of Torino, San Luigi Hospital, Orbassano, Torino, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Lo Iacono
authors.affiliation: Department of Oncology, University of Torino, San Luigi Hospital, Orbassano, Torino, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Bracco
authors.affiliation: Department of Oncology, University of Torino, San Luigi Hospital, Orbassano, Torino, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Busso
authors.affiliation: Department of Oncology, University of Torino, IRCCS Candiolo, Torino, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Di Blasio
authors.affiliation: Department of Oncology, University of Torino, IRCCS Candiolo, Torino, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Primo
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, San Luigi Hospital, Orbassano, Torino, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Peracino
authors.affiliation: Department of Oncology, University of Torino, San Luigi Hospital, Orbassano, Torino, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
authors.affiliation: Department of Oncology, University of Torino, San Luigi Hospital, Orbassano, Torino, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Scagliotti
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000069439:Dasatinib / Q000494:pharmacology*; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms; D008654:Mesothelioma; D000086002:Mesothelioma, Malignant; D000068437:Pemetrexed / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000069439:Dasatinib; D000068437:Pemetrexed; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D013940:Thymidylate Synthase
keywords: cell lines; dasatinib; malignant pleural mesothelioma; pemetrexed; thymidylate synthase