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

M Zuo; A Rashid; C Churi; J-N Vauthey; P Chang; Y Li; M-C Hung; D Li; M Javle

doi:10.1038/bjc.2014.625

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

Br J Cancer. 2015 Mar 17;112(6):1042-51. doi: 10.1038/bjc.2014.625.

Authors

M Zuo¹, A Rashid², C Churi¹, J-N Vauthey³, P Chang¹, Y Li¹, M-C Hung⁴, D Li¹, M Javle¹

Affiliations

¹ Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³ Department of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
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
Nanog Homeobox Protein
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / metabolism
Octamer Transcription Factor-3 / genetics
Octamer Transcription Factor-3 / metabolism
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
Xenograft Model Antitumor Assays
Zinc Finger Protein GLI1

Substances

Anilides
GLI1 protein, human
Hedgehog Proteins
HhAntag691
Homeodomain Proteins
NANOG protein, human
Nanog Homeobox Protein
Octamer Transcription Factor-3
Pyridines
Transcription Factors
Zinc Finger Protein GLI1
MTOR protein, human
Ribosomal Protein S6 Kinases, 70-kDa
TOR Serine-Threonine Kinases
Sirolimus