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, Francesco Leone

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)52354-52363
Number of pages10
JournalOncotarget
Volume7
Issue number32
DOIs
Publication statusPublished - Aug 1 2016

Fingerprint

Biliary Tract
Carcinoma
Heterografts
trametinib
Therapeutics
Growth
panitumumab
Neoplasms
Phosphorylation
Clinical Trials
Cell Line

Keywords

  • Biliary tract carcinoma
  • K-RAS mutation
  • MEK inhibitor
  • Preclinical models
  • Target therapy

ASJC Scopus subject areas

  • Oncology

Cite this

Preclinical activity of EGFR and MEK1/2 inhibitors in the treatment of biliary tract carcinoma. / Cavalloni, Giuliana; Peraldo-Neia, Caterina; Varamo, Chiara; Chiorino, Giovanna; Sassi, Francesco; Aglietta, Massimo; Leone, Francesco.

In: Oncotarget, Vol. 7, No. 32, 01.08.2016, p. 52354-52363.

Research output: Contribution to journalArticle

Cavalloni, Giuliana ; Peraldo-Neia, Caterina ; Varamo, Chiara ; Chiorino, Giovanna ; Sassi, Francesco ; Aglietta, Massimo ; Leone, Francesco. / Preclinical activity of EGFR and MEK1/2 inhibitors in the treatment of biliary tract carcinoma. In: Oncotarget. 2016 ; Vol. 7, No. 32. pp. 52354-52363.
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