Masitinib Combined with Standard Gemcitabine Chemotherapy: In Vitro and In Vivo Studies in Human Pancreatic Tumour Cell Lines and Ectopic Mouse Model

Abstract

BackgroundTyrosine kinases are attractive targets for pancreatic cancer therapy because several are over-expressed, including PDGFRα/β, 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, PDGFRα/β, 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.Methodology/FindingsProof-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 µM strongly sensitised Mia Paca2 cells to gemcitabine (>400-fold reduction in IC50); and moderately sensitised Panc1 cells (10-fold reduction). Transcriptional analysis identified the Wnt/β-catenin signalling pathway as down-regulated in the cell lines resensitised by the masitinib/gemcitabine combination.ConclusionsThese 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.

The Antipancreatic Cancer Activity of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2

“…As shown, in both transformed [PANC-1 and MIA PaCa2, both gemcitabine-resistant lines (Humbert et al, 2010)] and primary pancreatic cancer cells, gemcitabine (100 mM, 72 h) only exerted weak activity on cell survival ( Fig. 4A-C).…”

“…with 1 · 10 7 PANC-1 pancreatic cells, and treatment began 4 weeks (Humbert et al, 2010) post tumor implant with i.p. of gemcitabine (25 mg/kg, daily) with/without p.o.…”

Microvascular density and endothelial area correlate with Ki-67 proliferative index in surgically-treated pancreatic ductal adenocarcinoma patients

“…In addition, this anatomical link may be supported by the overexpression of several angiogenic cytokines, including vascular endothelial growth factor, fibroblast growth factor, thymidine phosphorylase and tryptase, which have been previously demonstrated to be present in PDAC tissue (32)(33)(34)(35). These cytokines, secreted from tumoral and stromal cells, have a role in the autocrine and paracrine growth stimulation of tumoral and endothelial cells (36)(37)(38).…”

Interplay Between Gemcitabine and Erlotinib Over Pancreatic Adenocarcinoma Cells

“…These results regarding the cytotoxic effect of the drugs coincided with others. [31][32][33][34][35][36][37][38] The relatively insensitivity of BxPC-3 to erlotinib has been reported by others as a consequence of the expression of elevated and constitutively phosphorylated ErbB3 levels. 39 Besides, the effects of erlotinib in combination with gemcitabine were considered, as others, 40 synergistic in k-ras-mutated pancreatic cancer cells (Panc-1), whereas it was considered antagonistic in k-ras wild-type pancreatic cancer cells (BxPC-3).…”