Abstract B153: CDK4/6 inhibitor synergizes with mTOR inhibitor to suppress cholangiocarcinoma pathogenesis

Abstract

Abstract Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer. It lacks effective therapies and is associated with high mortality rate as well as poor prognosis. Our recent study suggests that treatment of pan-mTOR inhibitor MLN0128 leads to stable disease in murine ICC model induced by activated AKT and Yap (AKT/YapS127A) via inducing apoptosis without affecting tumor cell proliferation. Palbociclib is a pan CDK4/6 inhibitor that has been approved by the FDA for the treatment of HR-positive advanced-stage breast cancer. However, its efficacy in ICC has not been investigated. ICC cells are known to be highly proliferative. Here we hypothesize that palbociclib is effective against ICC by inhibiting tumor cell proliferation. Furthermore, it may synergize with MLN0128 to inhibit ICC growth in vivo. We tested the therapeutic efficacy of palbociclib alone or in combination with MLN0128 in human ICC cell lines as well as in AKT/YapS127A ICC model. We found that in vitro palbociclib inhibits ICC cell growth via inhibiting cell cycle progression. The long-term cell growth, but not the short-term cell survival, to palbociclib is RB-dependent. Concomitant treatment of palbociclib with MLN0128 has a synergistic effect in inhibiting ICC cell viability. In AKT/YapS127A ICC preclinical model, treatment with palbociclib or MLN0128 alone all led to stable disease. In striking contrast, combined treatment of palbociclib with MLN0128 resulted in significant tumor regression. Mechanistically, we found that combined palbociclib with MLN0128 has a profound inhibitory effect in inhibiting ICC cell proliferation both in vivo and in vitro. In summary, our study suggests that palbociclib synergizes with MLN0128 to inhibit ICC cell proliferation, and combined treatment of palbociclib with MLN0128 represents promising novel therapeutics against this deadly malignancy. Citation Format: Xinhua Song, Xianqiong Liu, Jingxiao Wang, Xin Chen. CDK4/6 inhibitor synergizes with mTOR inhibitor to suppress cholangiocarcinoma pathogenesis [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 B153.