According to a recent study, anti-rejection drugs—immunosuppressants used after an organ transplant to ensure organ acceptance—can be repurposed to fight certain liver cancers with B-catenin mutations. The B-catenin gene plays an important role in the Wnt signaling pathway by regulating stem cell differentiation and cell fate decisions during development. Present in about 20% to 35% of liver cancer cases, B-catenin mutations are linked to various liver diseases.
"What we've found is that liver cancers with a specific mutation in the B-catenin gene are possibly more susceptible to rapamycin, a commonly used anti-rejection medication in transplantation," commented the senior author of the study, Satdarshan Monga, MD, Professor of Pathology and Director of the Pittsburgh Liver Research Center at the University of Pittsburgh's School of Medicine. "We think this gives us a new precision medicine approach to develop therapies for liver cancer, which often are very resistant to treatment."
Dr. Monga and colleagues discovered high levels of mTOR, a protein involved in cellular metabolism, while observing a ring of cells that surrounded the central vein found within the liver. Usually, B-catenin is found in the area in which the researchers found the high levels of mTOR.
The scientists created a mouse model of liver cancer with B-catenin and mutations of MET, a gene that encodes a member of the receptor tyrosine kinase family. Mutations in the MET gene are associated with liver cancer. They discovered that B-catenin activated mTOR using glutamine synthase (GS), an enzyme that controls nitrogen levels in cells. Activity levels of GS and mTOR were elevated in cancer cells in order to increase energy so that the cancer cells could grow.
"I like to say these tumors are mTOR addicted," said Dr. Monga. "Activating mTOR kicks up the protein-making factories in these cells, giving them the resources to divide and grow."
When the investigators administered rapamycin, an anti-rejection drug that inhibits mTOR, the mice's tumors decreased in size. This result shows that mTOR plays an important role in helping liver tumors grow. When the researchers also gave the mice a drug that inhibited the MET gene, the tumors almost diminished completely.
In addition, anti-rejection drugs could be used for patients who undergo liver transplants.
"While transplant patients are prescribed either rapamycin or a different immunosuppressant, those that have B-catenin–mutated and mTOR-addicted tumors might benefit from using rapamycin as the preferred anti-rejection medication. We hope to conduct clinical trials in the near future to test rapamycin both in treating liver cancer and to prevent its recurrence in patients receiving liver transplants," Dr. Monga stated.
For More Information
Michael AOA, Ko S, Tao J, et al (2019). Inhibiting glutamine-dependent mTORC1 activation ameliorates liver cancers driven by b-catenin mutations. Cell Metab. [Epub ahead of print] DOI:10.1016/j.cmet.2019.01.002
Image courtesy of TexasPathologistMSW