Cancer cells pose an uncanny ability to make new cells and dodge drugs, "somewhat like would-be robbers hacking the bank's alarm code," one doctor explains. But researchers at Cincinnati Children's Hospital Medical Center have figured out how cancer cells rewire themselves and, in turn, how to possibly overcome drug resistance.
This drug resistance may explain why some acute myeloid leukemia (AML) and other cancer patients suffer fatal relapses despite many improvements in leukemia outcomes over the years, according to a Children's news release.
"Overcoming resistance to therapy remains a holy grail of leukemia treatment," says Yi Zheng, Ph.D., director, experimental hematology and cancer biology at Cincinnati Children's. Zheng and his colleagues have now discovered a way to boost the effectiveness of mTOR inhibitors, which prohibit unwanted cell proliferation.
"While the latest study is based on mouse models, building upon the findings published Dec. 21, 2020, in PNAS eventually could improve outcomes for people with AML, and possibly other forms of cancer," a release says.
What Happens When Treatments Target mTOR?
"Using a novel mouse model, we have learned that deleting the mTOR gene prompts blood stem cells to multiply rapidly to open other pathways to continue producing new blood cells," says Zheng, the study's senior author. "We also found that leukemia cells use a similar response to continue multiplying despite mTOR-inhibiting treatments."
He says attacking mTOR essentially sets off alarms among hemopoietic stem cells (HSCs), which act like blood cell factories deep in bone marrow. Then the cells themselves produce a flood of new, re-wired blood cells. These re-wired stem cells, treated with mTOR inhibitors, can begin multiplying, rendering mTOR inhibitor drugs useless.
The co-authors say mTOR treatment resistance can be counteracted by inhibiting activity of the MNK, CDK9 or c-Myc genes. So-called BET inhibitors can act against c-Myc activity. Other inhibitors that are in clinical trials can act against CDK9.
Scientists at Cincinnati Children’s have already launched some of the research needed to prepare the combination therapies for in vivo test leading to human clinical trials, the news release says. That process will take time, but since mTOR inhibitors have been widely tested in clinical trials, investigators have a head start on exploring combination therapies.
Longer term, the findings may extend beyond AML, Zheng says, because mTOR has been a recognized target in most human cancers, including solid tumors like brain tumors.