| RRC ID |
62769
|
| 著者 |
Cavalloni G, Peraldo-Neia C, Varamo C, Chiorino G, Sassi F, Aglietta M, Leone F.
|
| タイトル |
Preclinical activity of EGFR and MEK1/2 inhibitors in the treatment of biliary tract carcinoma.
|
| ジャーナル |
Oncotarget
|
| Abstract |
Biliary tract carcinomas (BTC) are malignant tumors with limited therapeutic options. Clinical experiences with anti-EGFR therapies have produced unsatisfactory results. The strategies of combined inhibition of EGFR and MEK1/2 could be a promising therapeutic option in BTC treatment. Preclinical activity of Panitumumab and Trametinib was tested in in vitro (EGI-1, MT-CHC01 and WITT cells) and in in vivo (xenograft) BTC models with different K-RAS mutational status. Trametinib reduced MAPK phosphorylation in wild type (WT) WITT cells and in both K-RAS mutated cells; in EGI-1 was also able to switch off EGFR activation. Panitumumab reduced the activation of its target only in EGI-1 cells, and of MAPK only in WITT cells. While Trametinib inhibited cell growth in K-RAS mutated cell lines, Panitumumab had no effect on proliferation independently by K-RAS status. The addition of Panitumumab to Trametinib did not significantly potentiate its anti-proliferative effect also in mutated cells. In vivo, Trametinib was able to significantly slow the tumor growth in K-RAS mutated xenograft models, but did not have effect on K-RAS WT cells; the addition of Panitumumab potentiated the Trametinib efficacy in MT-CHC01 and overcame the resistance to the anti-EGFR in WITT cells, in which the monotherapy was ineffective. Only in K-RAS mutated xenografts Trametinib alone or in combination with Panitumumab significantly decreased Ki67 positive cell fraction and CD31 angiogenesis markers. In conclusion, this preclinical study provides a rational to plan clinical trials assessing the efficacy of Trametinib in K-RAS mutated BTC patients and the combination with anti-EGFR in WT BTC patients.
|
| 巻・号 |
7(32)
|
| ページ |
52354-52363
|
| 公開日 |
2016-8-9
|
| DOI |
10.18632/oncotarget.10587
|
| PII |
10587
|
| PMID |
27429047
|
| PMC |
PMC5239557
|
| MeSH |
Animals
Antibodies, Monoclonal / pharmacology*
Antineoplastic Agents / pharmacology*
Biliary Tract Neoplasms*
Cell Line, Tumor
Cell Proliferation / drug effects
ErbB Receptors / antagonists & inhibitors
Female
Humans
MAP Kinase Kinase Kinase 1 / antagonists & inhibitors
MAP Kinase Kinase Kinase 2 / antagonists & inhibitors
Mice
Mice, Inbred NOD
Mice, SCID
Panitumumab
Protein Kinase Inhibitors / pharmacology
Pyridones / pharmacology*
Pyrimidinones / pharmacology*
Xenograft Model Antitumor Assays
|
| IF |
5.168
|
| リソース情報 |
| ヒト・動物細胞 |
TGBC1TKB(RCB1129) |
