Hedgehog and mTOR pathways converge in oesophageal cancer
Crosstalk between two pathways and potential combination therapy
- Date : 26 Mar 2012
- Topic : Gastrointestinal cancers
Identification of a non-traditional pathway for spiriting a cancer-promoting protein into the cell nucleus points to a possible new combination therapy for oesophageal cancer and indicates a mechanism of resistance for new drugs that attack the Hedgehog pathway. A team of researchers at The University of Texas MD Anderson Cancer Centre reports in the March 20 issue of Cancer Cell that the mTOR molecular pathway promotes the activity of the Gli1 protein in oesophageal cancer development and progression.
The Hedgehog pathway is the established, or canonical, pathway for activating Gli1. According to senior author Mien-Chie Hung, PhD, vice president for basic research, professor and chair of MD Anderson's Department of Molecular and Cellular Oncology, the study team has shown a clear-cut mechanism to link all non-canonical activation of Gli1 through a single pathway, TOR. The study experiments showed that a combination of the mTOR inhibitor everolimus and the Hedgehog inhibitor GDC-0449 steeply reduced the tumour burden in a mouse model of oesophageal adenocarcinoma. Both drugs have been approved by the USA Food and Drug Administration but for use in other types of cancer.
Both pathways active in aggressive human cancer
An analysis of 107 tissue samples of human oesophageal cancer tumours showed that 80 (74.8%) had a marker of mTOR promotion of Gli1 and 87 (81.3%) had the version of Gli1 activated by Hedgehog.
Oesophageal cancer is one of the most aggressive forms of cancer, with fewer than 20% of patients surviving for five years, the study notes. Inflammation and obesity are thought to be driving factors in its increased incidence.
The researchers used experiments with cell lines, mouse models and human tumour samples to demonstrate how Hedgehog and mTOR, both implicated in oesophageal and a variety of cancers, converge on Gli1.
Slipping Gli1 into the nucleus
Gli1 is a transcription factor - a protein that moves into the cell nucleus where it binds to and activates other genes. Gli1 normally is held out of the nucleus by a protein called SuFu, which binds to it at a specific region.
The Hedgehog pathway frees Gli1 by activating a signalling protein called Smoothened (SMO), which blocks SuFu binding, allowing Gli1 to move into the nucleus and activate a variety of genes, including Hedgehog activators.
GDC-0449, approved in January by the FDA for treatment of metastatic basal cell carcinoma, inhibits SMO. Basal cell carcinoma is driven by mutations in the Hedgehog pathway, but resistance to SMO inhibitors has emerged in clinical trials to treat other cancers, such as ovarian and pancreas.
How mTOR helps Gli1
Hung and colleagues started with Tumour Necrosis Factor Alpha (TNFa), an inflammatory protein connected to the development of oesophageal cancer. In a series of experiments, they found that TNFa triggers Gli1 through the mTOR pathway by:
- Activating the kinase S6K1, which attaches a phosphate group to Gli1 rendering the phosphorylated Gli1 unable to bind to SuFu.
- With SuFu thwarted, the phosphorylated version of Gli1 moves into the nucleus and activates genes.
The team developed an antibody to identify the presence of phosphorylated Gli1, providing a possible biomarker of cancer resistant to Hedgehog inhibitors.
The team treated mice with oesophageal cancer with RAD-001, GDC-0449 or both. The mTOR inhibitor RAD-001 alone had almost no effect. The Hedgehog inhibitor GDC-0449 alone reduced tumour volume by 40%. Together, they reduced tumour volume by 90%.
Clinical trials of the combination for oesophageal and other cancers could be guided by the antibody for phosphorylated Gli1 and the presence of plain Gli1, which would indicate a need to use both drugs.
Earlier research by other labs indicates that the AKT and MAPK/ERK also activate the Hedgehog pathway. Hung and colleagues show that AKT and ERK, which both activate the mTOR pathway, appear to activate Gli1 via phosphorylation of S6K1 and Gli1.
Funding for this research was provided by grants from the USA National Cancer Institute, including MD Anderson's Cancer Centre Support Grant; The Kadoorie Charitable Foundation; Susan G. Komen for the Cure; the Sister Institution Fund of China Medical University and Hospital and MD Anderson; the Department of Health Cancer Research Centre of Excellence, Taiwan; MD Anderson's Centre for Multidisciplinary Research Program, and the Delmer Dallas Endowed Research Fund in Gastrointestinal Cancers; Mr. and Mrs. Raymond P. Park, Dr. Abdul Aziz Sultan, Susan J. Smith and Carlos Cantu family funds, the River Creek Foundation, Schecter Family Foundation and the Kevin Frankel and Gary W. Frazier Funds.
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