title: Preclinical activity of EGFR and MEK1/2 inhibitors in the treatment of biliary tract carcinoma.
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.
authors.affiliation: Medical Oncology Division, Fondazione del Piemonte per l'Oncologia (FPO), Candiolo Cancer Institute IRCCS, Candiolo, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cavalloni
authors.affiliation: Department of Oncology, University of Turin, Candiolo Cancer Institute IRCCS, Candiolo, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Peraldo-Neia
authors.affiliation: Department of Oncology, University of Turin, Candiolo Cancer Institute IRCCS, Candiolo, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Varamo
authors.affiliation: Cancer Genomics Laboratory, Fondazione Edo ed Elvo Tempia Valenta, Biella, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Chiorino
authors.affiliation: Unit of Molecular Pharmacology, University of Turin Medical School, Candiolo Cancer Institute IRCCS, Candiolo, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sassi
authors.affiliation: Medical Oncology Division, Fondazione del Piemonte per l'Oncologia (FPO), Candiolo Cancer Institute IRCCS, Candiolo, Italy.|Department of Oncology, University of Turin, Candiolo Cancer Institute IRCCS, Candiolo, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Aglietta
authors.affiliation: Medical Oncology Division, Fondazione del Piemonte per l'Oncologia (FPO), Candiolo Cancer Institute IRCCS, Candiolo, Italy.|Department of Oncology, University of Turin, Candiolo Cancer Institute IRCCS, Candiolo, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Leone
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001661:Biliary Tract Neoplasms; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048730:MAP Kinase Kinase Kinase 2 / Q000037:antagonists & inhibitors; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000077544:Panitumumab; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D000077544:Panitumumab; C512478:EGFR protein, human; D066246:ErbB Receptors; D048728:MAP Kinase Kinase Kinase 1; D048730:MAP Kinase Kinase Kinase 2
keywords: K-RAS mutation; MEK inhibitor; biliary tract carcinoma; preclinical models; target therapy