Novel therapeutic strategy targeting the Hedgehog signalling and mTOR pathways in biliary tract cancer.
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.
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
M
M
Zuo
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
A
A
Rashid
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
C
C
Churi
Department of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
J-N
JN
Vauthey
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
P
P
Chang
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Y
Y
Li
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
M-C
MC
Hung
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
D
D
Li
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
M
M
Javle
D000813:Anilides / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001661:Biliary Tract Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000071676:Zinc Finger Protein GLI1
D000813:Anilides; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; C538724:HhAntag691; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; D011725:Pyridines; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus