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.
Highlights
Cholangiocarcinoma (CCA) is a type of malignancy with tumor cells arising within the liver or bile ducts with features of cholangiocyte differentiation[1,2]
Our study suggests the efficacy of MEK inhibitors against K-Ras mutant Intrahepatic cholangiocarcinoma (iCCA), supporting the further development of drugs targeting MEK1/2 for the treatment of K-Ras mutant iCCA
K-Ras mutant human CCA cell lines are highly sensitive to MEK inhibitors As a first step to evaluate the therapeutic potential of MEK inhibitors for the treatment of iCCA, we collected seven human CCA cell lines
Summary
Cholangiocarcinoma (CCA) is a type of malignancy with tumor cells arising within the liver or bile ducts with features of cholangiocyte differentiation[1,2]. The incidence rate of CCA has been raising in the Western world[3,4]. CCA can be classified as intrahepatic (iCCA), perihilar (pCCA), and distal cholangiocarcinoma (dCCA). ICCA is a deadly malignancy with limited treatment options. Surgical resection iCCA are lacking, iCCA remains a deadly malignancy with a 5-year survival rate lower than 10%6. Gain-of-function mutations of the K-Ras gene represent one of the most frequent alterations in iCCA. Multiple studies indicate that K-Ras mutations could be found in ~15–25% of human iCCAs7–10. Activated K-Ras mutations lead to constitutive hyper-activation of the Raf-
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