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Efficacy of MEK inhibition in a K-Ras-driven cholangiocarcinoma preclinical model.

  • Author(s): Dong, Mingjie;
  • Liu, Xianqiong;
  • Evert, Katja;
  • Utpatel, Kirsten;
  • Peters, Michele;
  • Zhang, Shanshan;
  • Xu, Zhong;
  • Che, Li;
  • Cigliano, Antonio;
  • Ribback, Silvia;
  • Dombrowski, Frank;
  • Cossu, Antonio;
  • Gordan, John;
  • Calvisi, Diego F;
  • Evert, Matthias;
  • Liu, Yan;
  • Chen, Xin
  • et al.
Abstract

Intrahepatic cholangiocarcinoma (iCCA) is a deadly malignancy with limited treatment options. Gain-of-function mutations in K-Ras is a very frequent alteration, occurring in ~15 to 25% of human iCCA patients. Here, we established a new iCCA model by expressing activated forms of Notch1 (NICD) and K-Ras (K-RasV12D) in the mouse liver (K-Ras/NICD mice). Furthermore, we investigated the therapeutic potential of MEK inhibitors in vitro and in vivo using human CCA cell lines and K-Ras/NICD mice, respectively. Treatment with U0126, PD901, and Selumetinib MEK inhibitors triggered growth restraint in all CCA cell lines tested, with the most pronounced growth suppressive effects being observed in K-Ras mutant cells. Growth inhibition was due to reduction in proliferation and massive apoptosis. Furthermore, treatment of K-Ras/NICD tumor-bearing mice with PD901 resulted in stable disease. At the molecular level, PD901 efficiently inhibited ERK activation in K-Ras/NICD tumor cells, mainly leading to increased apoptosis. Altogether, our study demonstrates that K-Ras/NICD mice represent a novel and useful preclinical model to study K-Ras-driven iCCA development and the effectiveness of MEK inhibitors in counteracting this process. Our data support the usefulness of MEK inhibitors for the treatment of human iCCA.

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