Abstract A212: Preclinical efficacy of MEK inhibition in a K-Ras driven cholangiocarcinoma preclinical model

Abstract

Abstract Intrahepatic cholangiocarcinoma (iCCA) is a form of deadly malignancy with limited treatment options. Gain-of-function mutations in KRAS are one of the most frequent mutations, found in ~25% of human CCA patients. MEK inhibitors have been developed and show some activity against solid tumors with Ras mutants. However, whether MEK inhibitors are effective against KRas mutant CCAs remains unknown. In the current study, we established a new mouse iCCA model (NICD/KRas) by expressing activated forms of Notch (NICD) and KRas (KRasV12D). We investigated the therapeutic potential of MEK inhibitors in vitro using human CCA cell lines and in vivo using KRasV12/NICD iCCA preclinical model. We found that in general, CCA cell lines with KRas mutations are more sensitive to MEK inhibitor U0126. Treatment of U0126 in KRas mutant CCA cells leads to increased apoptosis and decreased expression of pro-apoptosis gene Survivin. Furthermore, we found that treating KRasV12/NICD tumor-bearing mice with MEK inhibitor PD0325901 (PD901) resulted in stable disease. At molecular levels, PD901 efficiently inhibited p-ERK expression KRasV12/NICD tumor cells, leading to increased apoptosis. In summary, our studies demonstrate that KRasV12/NICD mice represent a novel and useful preclinical model to study KRas-driven CCA development. Our data further support the usefulness of MEK inhibitors for treatment of KRas mutant CCA in patients. Citation Format: Mingjie Dong, Xianqiong Liu, Katja Evert, Kirsten Utpatel, Shanshan Zhang, Li Che, John Gordan, Diego Calvisi, Matthias evert, Yan Liu, Xin Chen. Preclinical efficacy of MEK inhibition in a K-Ras driven cholangiocarcinoma preclinical model [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A212.