title: Masitinib combined with standard gemcitabine chemotherapy: in vitro and in vivo studies in human pancreatic tumour cell lines and ectopic mouse model.
abstract: BACKGROUND
  Tyrosine kinases are attractive targets for pancreatic cancer therapy because several are over-expressed, including PDGFRalpha/beta, FAK, Src and Lyn. A critical role of mast cells in the development of pancreatic cancer has also been reported. Masitinib is a tyrosine kinase inhibitor that selectively targets c-Kit, PDGFRalpha/beta, Lyn, and to a lesser extent the FAK pathway, without inhibiting kinases of known toxicities. Masitinib is particularly efficient in controlling the proliferation, differentiation and degranulation of mast cells. This study evaluates the therapeutic potential of masitinib in pancreatic cancer, as a single agent and in combination with gemcitabine.
  
  
  RESULTS
  Proof-of-concept studies were performed in vitro on human pancreatic tumour cell lines and then in vivo using a mouse model of human pancreatic cancer. Molecular mechanisms were investigated via gene expression profiling. Masitinib as a single agent had no significant antiproliferative activity while the masitinib/gemcitabine combination showed synergy in vitro on proliferation of gemcitabine-refractory cell lines Mia Paca2 and Panc1, and to a lesser extent in vivo on Mia Paca2 cell tumour growth. Specifically, masitinib at 10 microM strongly sensitised Mia Paca2 cells to gemcitabine (>400-fold reduction in IC(50)); and moderately sensitised Panc1 cells (10-fold reduction). Transcriptional analysis identified the Wnt/beta-catenin signalling pathway as down-regulated in the cell lines resensitised by the masitinib/gemcitabine combination.
  
  
  CONCLUSIONS
  These data establish proof-of-concept that masitinib can sensitise gemcitabine-refractory pancreatic cancer cell lines and warrant further in vivo investigation. Indeed, such an effect has been recently observed in a phase 2 clinical study of patients with pancreatic cancer who received a masitinib/gemcitabine combination.
authors.affiliation: AB Science SA, Paris, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Humbert
authors.forename: Nathalie
authors.initials: N
authors.lastname: Castéran
authors.forename: Sébastien
authors.initials: S
authors.lastname: Letard
authors.forename: Katia
authors.initials: K
authors.lastname: Hanssens
authors.forename: Juan
authors.initials: J
authors.lastname: Iovanna
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.forename: Thomas
authors.initials: T
authors.lastname: Bader
authors.forename: Colin D
authors.initials: CD
authors.lastname: Mansfield
authors.forename: Alain
authors.initials: A
authors.lastname: Moussy
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.forename: Patrice
authors.initials: P
authors.lastname: Dubreuil
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D010880:Piperidines; D011725:Pyridines; D013844:Thiazoles / Q000008:administration & dosage; D000093542:Gemcitabine
chemical_list: D001549:Benzamides; D010880:Piperidines; D011725:Pyridines; D013844:Thiazoles; D003841:Deoxycytidine; C526575:masitinib; D000093542:Gemcitabine