Oncotarget

Research Papers:

Preclinical activity of EGFR and MEK1/2 inhibitors in the treatment of biliary tract carcinoma

Giuliana Cavalloni, Caterina Peraldo-Neia, Chiara Varamo, Giovanna Chiorino _, Francesco Sassi, Massimo Aglietta and Francesco Leone

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Oncotarget. 2016; 7:52354-52363. https://doi.org/10.18632/oncotarget.10587

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Abstract

Giuliana Cavalloni1, Caterina Peraldo-Neia2, Chiara Varamo2, Giovanna Chiorino3, Francesco Sassi4, Massimo Aglietta1,2, Francesco Leone1,2

1Medical Oncology Division, Fondazione del Piemonte per l’Oncologia (FPO), Candiolo Cancer Institute IRCCS, Candiolo, Italy

2Department of Oncology, University of Turin, Candiolo Cancer Institute IRCCS, Candiolo, Italy

3Cancer Genomics Laboratory, Fondazione Edo ed Elvo Tempia Valenta, Biella, Italy

4Unit of Molecular Pharmacology, University of Turin Medical School, Candiolo Cancer Institute IRCCS, Candiolo, Italy

Correspondence to:

Giuliana Cavalloni, email: [email protected]

Keywords: biliary tract carcinoma, K-RAS mutation, target therapy, MEK inhibitor, preclinical models

Received: March 30, 2016     Accepted: June 17, 2016     Published: July 13, 2016

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.


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