Modulation of mTOR and Epigenetic Pathways as Therapeutics in Gallbladder Cancer

Abstract Gallbladder cancer (GBC) is the most common malignancy of the biliary tract with extremely dismal prognosis. Limited therapeutic options are available for gallbladder cancer patients. We used whole exome sequencing of human gallbladder cancer to identify the ErbB and epigenetic pathways as two vulnerabilities in GBC. We screened two focused small molecule libraries that target these two pathways using gallbladder cancer cell lines and identified the mTOR inhibitor INK-128 and the HDAC inhibitor JNJ-26481585 as compounds that inhibited proliferation at low concentrations. Both significantly suppressed tumor growth and metastases in mouse models. Both synergized with the standard of care chemotherapeutic agent gemcitabine in cell lines and in mouse models. Furthermore, the activation of mTOR pathway, measured by immunostaining for phosphorylated mTOR and downstream effector S6K1, is correlated with poor prognosis in gallbladder cancer. Phosphorylated mTOR or p-S6K1 in clinical samples is independent indicator for overall survival in gallbladder cancer patients. Taken together, our findings suggest that mTOR inhibitors and HDAC inhibitors can serve as potential therapeutics for gallbladder cancer and the phosphorylation of mTOR and S6K1 may serve as biomarkers for gallbladder cancer.