Diep CH, Munoz RM, Choudhary A, Von Hoff DD, Han H. "Clin Cancer Res. 2011 May"
PURPOSE:
The mixture of erlotinib and gemcitabine has shown a modest but statistically substantial survival benefit compared with gemcitabine on your own in individuals with superior pancreatic most cancers. Nevertheless, the all round survival price using the erlotinib and gemcitabine mixture is nonetheless reduced.
In this study, we sought to identify gene targets that, when inhibited, would boost the activity of epidermal development element receptor (EGFR)-targeted therapies in pancreatic cancer cells.
EXPERIMENTAL Style:
A high-throughput RNA-interference(RNAi) display was completed to determine candidate genes. Selected gene hits had been further verified and mechanisms of action were additional investigated utilizing different assays.
RESULTS:
Six gene hits from siRNA screening were confirmed to drastically sensitize BxPC-3 pancreatic cancer cells to erlotinib. Among the hits, mitogen-activated protein kinase (MAPK) one, was selected for additional mechanistic studies. Mixture remedies of erlotinib and two MAP kinases, MEK inhibitors, RDEA119 and AZD6244, showed significant synergistic impact for both combinations (RDEA119-erlotinib and AZD6244-erlotinib) in comparison using the corresponding single drug treatments in pancreatic most cancers cell lines with wild-type KRAS (BxPC-3 and Hs 700T) but not in cell lines with mutant KRAS (MIA PaCa-2 and PANC-1).
The enhanced antitumor exercise with the combination treatment was further verified inside the BxPC-3 and MIA PaCa-2 mouse xenograft product. Examination from the MAPK signaling pathway by Western blotting indicated efficient inhibition in the EGFR signaling by the drug combination in KRAS wild-type cells although not in KRAS mutant cells.
CONCLUSIONS:
Overall, our outcomes suggest that mixture treatment of an EGFR and MEK inhibitors may have enhanced efficacy in individuals with pancreatic most cancers.
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