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2016
Journal Article
Titel
Targeted therapies of two different Braf mutated colorectal carcinoma cell lines and the establishment of a 3D tumor model on the basis of a decellularized intestinal matrix
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Abstract
Abstract
Vemurafenib is a potent inhibitor of BRAF in braf mutant melanomas but shows response rates of just about 5% in Braf mutant colorectal carcinomas (CRCs) (Corcoran et al. 2012). It has been reported that the inhibition of BRAF increases the phosphorylation of the epidermal growth factor receptor (EGFR) via a feedback loop in CRC cell lines (Prahallad et al. 2012). Thus, we tested combination therapies with vemurafenib and the EGFR inhibitor gefitinib as well as the effect of the PI3K inhibitor LY294002 to block the PI3K/Akt/mTOR pathway. We used different combinations of all three inhibitors in two cell lines (HROC24, HROC87) carrying a Braf mutation (V600E) but differing in other mutations (Maletzki et al. 2012). In conventional 2D cell culture, vemurafenib mono-treatment increased apoptosis rate in HROC24 but not in HROC87 cells, whereas gefitinib or LY294002 alone did not show an effect. The combination of two or three drugs was more efficient than the respective mono-therapy in HROC87 but not in HROC24 cells. In 3D cell culture, the combination of drugs does not show an increase in apoptosis rate compared to the mono-treatment. This leads to the conclusion that the determination of a single genetic lesion is not always sufficient to choose the most effective therapy. In general, it is reported that 3D tumor models are more resistant to chemotherapies than 2D cell culture models and that they show more reliable results in drug testing (Stratmann et al. 2013). For this reason, we established a 3D model on a decellularized intestinal scaffold to compare the effect of drugs on apoptosis, proliferation and pathway signaling with common 2D cell culture. We conclude that our 3D test system is a reliable model to test new therapies for the treatment of cancer.
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