Novel therapeutic strategy targeting the Hedgehog signalling and mTOR pathways in biliary tract cancer

• Published in: British journal of cancer 2015-03, Vol.112 (6), p.1042-1051
• Main Authors: Zuo, M, Rashid, A, Churi, C, Vauthey, J-N, Chang, P, Li, Y, Hung, M-C, Li, D, Javle, M
• Format: Article
• Language: English
• Subjects: 631/80/86; 692/699/67/1059/602; 692/699/67/1504/1329; 692/700/565/1436/1437; Anilides - administration & dosage; Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biliary Tract Neoplasms - drug therapy; Biliary Tract Neoplasms - genetics; Biliary Tract Neoplasms - metabolism; Biliary Tract Neoplasms - pathology; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Drug Resistance; Epidemiology; G1 Phase - drug effects; G1 Phase - genetics; Gene Expression Profiling; Hedgehog Proteins - antagonists & inhibitors; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Mice; Mice, Nude; Molecular Medicine; Nanog Homeobox Protein; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Octamer Transcription Factor-3 - genetics; Octamer Transcription Factor-3 - metabolism; Oncology; Pyridines - administration & dosage; Ribosomal Protein S6 Kinases, 70-kDa - genetics; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Signal Transduction - drug effects; Sirolimus - administration & dosage; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Translational Therapeutics; Xenograft Model Antitumor Assays; Zinc Finger Protein GLI1
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2014.625

Background: Activation of the PI3K/mTOR and Hedgehog (Hh) signalling pathways occurs frequently in biliary tract cancer (BTC). Crosstalk between these pathways occurs in other gastrointestinal cancers. The respective signalling inhibitors rapamycin and vismodegib may inhibit BTC synergistically and suppress cancer stem cells (CSCs). Methods: Gene expression profiling for p70S6k and Gli1 was performed with BTC cell lines. Tumour and pathway inhibitory effects of rapamycin and vismodegib were investigated in BTC preclinical models and CSCs. Results: Rapamycin and vismodegib synergistically reduced BTC cell viability and proliferation. This drug combination arrested BTC Mz-ChA-1 cells in the G1 phase but had no significant effect on the cell cycle of BTC Sk-ChA-1 cells. Combined treatment inhibited the proliferation of CSCs and ALDH-positive cells. Nanog and Oct-4 expression in CSCs was decreased by the combination treatment. Western blotting results showed the p-p70S6K, p-Gli1, p-mTOR, and p-AKT protein expression were inhibited by the combination treatment in BTC cells. In an Mz-ChA-1 xenograft model, combination treatment resulted in 80% inhibition of tumour growth and prolonged tumour doubling time. In 4 of 10 human BTC specimens, tumour p-p70S6K and Gli1 protein expression levels were decreased with the combination treatment. Conclusions: Targeted inhibition of the PI3K/mTOR and Hhpathways indicates a new avenue for BTC treatment with combination therapy.