TAMPA, Fla. – Mutations in the KRas gene are commonly found in many types of cancer, including pancreatic, lung and colorectal cancer. However, KRas is considered a difficult protein to target with drugs, and to date, no specific KRas inhibitor have reached clinical trials. Researchers at Moffitt Cancer Center are trying to devise alternative mechanisms to block KRas. Their recent study demonstrates that the protein GSK3 is an important mediator of KRas-dependent tumor viability. Their research was published today in Nature Communications.
KRas was one of the first genes identified as being an important contributor to cancer development and progression. Thirty years ago, scientists discovered that mutations in KRas can lead to the development of cancer. Since that time, studies have shown that KRas mutations also contribute to drug resistance, and patients who have mutations in the KRas gene tend to have a poor prognosis. Given the importance of KRas to cancer, numerous attempts have been made to design KRas-targeting drugs; however, despite promising preclinical data, no direct KRas inhibitors are available to cancer patients.
A team of Moffitt researchers, led by Saïd Sebti, Ph.D., performed an extensive set of laboratory experiments to identify an indirect mechanism to target and inhibit KRas-dependent cancer. The researchers compared two sets of human cancer cell lines that both had mutations in the KRas gene; however, one set was dependent on KRas for survival and growth, while the second set was able to survive without KRas. They discovered that the Kinase GSK3 was necessary for survival in the KRas-dependent cell line, and that suppression of GSK3 inhibits tumor growth by increasing the levels of β-Catenin and c-Myc. These observations suggest that GSK3 may have a pro-survival role in KRas-dependent cancers, and that it may be possible to target GSK3 to promote cell death in these tumor types.
In order to confirm this hypothesis, the researchers performed experiments in cell lines and mice to inhibit GSK3. These revealed that blocking GSK3 with drugs or gene-targeted approaches stimulated cell death and reduced tumor growth in mice. The researchers also demonstrated that inhibition of GSK3 reduced tumor growth in mice from tumors derived from pancreatic cancer patients who relapsed after radiation or chemotherapy.
These findings demonstrate a potential solution to the challenges of targeting KRas in patients.
“This study discovered a novel vulnerability in mutant KRas-addicted human cancers. We have uncovered an essential link between GSK3 activity and mutant KRas dependency that is highly relevant in many aggressive and end-stage cancers. This discovery opens new avenues to target mutant KRas-addicted cancers,” said Sebti, study author and senior member of the Drug Discovery Department at Moffitt.
The study was funded in part by a grant from the National Institutes of Health (R35 CA197731-01) and was supported in part by the Chemical Biology, Molecular Genomics and SAIL Core Facilities at Moffitt (P30-CA076292).
About Moffitt Cancer Center
Moffitt is dedicated to one lifesaving mission: to contribute to the prevention and cure of cancer. The Tampa-based facility is one of only 49 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt’s scientific excellence, multidisciplinary research, and robust training and education. Moffitt is a Top 10 cancer hospital and has been nationally ranked by U.S. News & World Report since 1999. Moffitt devotes more than 2 million square feet to research and patient care. Moffitt’s expert nursing staff is recognized by the American Nurses Credentialing Center with Magnet® status, its highest distinction. With more than 6,000 team members, Moffitt has an economic impact in the state of $2.1 billion. For more information, call 1-888-MOFFITT (1-888-663-3488), visit MOFFITT.org, and follow the momentum on Facebook, Twitter andYouTube.