Back to Search
Start Over
Modulation of mTOR and epigenetic pathways as therapeutics in gallbladder cancer
- Source :
- Molecular Therapy: Oncolytics, Vol 20, Iss, Pp 59-70 (2021), Molecular Therapy Oncolytics
- Publication Year :
- 2021
- Publisher :
- Elsevier, 2021.
-
Abstract
- Gallbladder cancer (GBC) is the most common malignancy of the biliary tract, with extremely dismal prognosis. Limited therapeutic options are available for GBC patients. We used whole-exome sequencing of human GBC 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 GBC cell lines and identified the mTOR inhibitor INK-128 and the histone deacetylase (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 the mTOR pathway, measured by immunostaining for phosphorylated mTOR and downstream effector S6K1, is correlated with poor prognosis in GBC. Phosphorylated mTOR or p-S6K1 in clinical samples is an independent indicator for overall survival in GBC patients. Taken together, our findings suggest that mTOR inhibitors and HDAC inhibitors can serve as potential therapeutics for GBC, and the phosphorylation of mTOR and S6K1 may serve as biomarkers for GBC.<br />Graphical Abstract<br />Gallbladder cancer is the most common malignancy of biliary tract, with dismal prognosis. We identified mTOR and HDAC as two potential therapeutic targets and proved p-mTOR and p-S6K1 may serve as biomarkers, which opens opportunities for the development of new targeted therapeutics for gallbladder cancer patients.
- Subjects :
- 0301 basic medicine
Cancer Research
P70-S6 Kinase 1
Malignancy
lcsh:RC254-282
03 medical and health sciences
0302 clinical medicine
ErbB
medicine
Pharmacology (medical)
Epigenetics
Gallbladder cancer
PI3K/AKT/mTOR pathway
business.industry
medicine.disease
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Gemcitabine
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Cancer research
Molecular Medicine
Original Article
Histone deacetylase
business
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 23727705
- Volume :
- 20
- Database :
- OpenAIRE
- Journal :
- Molecular Therapy: Oncolytics
- Accession number :
- edsair.doi.dedup.....08392c998a0c117858482dec80749a07