Researchers from UCLA's Jonsson Comprehensive Cancer Center have discovered a biological mechanism that makes brain tumor cells drug resistant by allowing them to escape from the drugs designed to target them. The study was published online Dec. 5 by the journal Science.
Glioblastoma is the most common and deadliest form of brain cancer, and the surface of its cells are marked by telltale mutations that accelerate tumor growth. The drugs currently used to find and kill glioblastoma cells target those mutations.
Led by first author David Nathanson, assistant professor of molecular and medical pharmacology at UCLA, and former UCLA professor Paul Mischel, now at the Ludwig Institute for Cancer Research at UC San Diego, the researchers found that the tumor cells temporarily eliminate the gene mutation when they sense the presence of the cancer drug, essentially removing the drug's target and allowing the tumor to become drug resistant.
Remarkably, the study also found that after the drug is removed, the tumor cells reacquire the gene mutation (called an oncogene) that helps the tumor cells grow more robustly, and that they can repeat this cycle as often as the drug is given. Importantly, that ability is what could make the cancer cells vulnerable to the original therapy: Doctors may be able to use pulsative drug delivery, for example, to take better advantage of the periods when the cancer cells are sensitized to the drugs.
"Now that we know that tumor cells have the surprising capacity to lose this oncogene during treatment and then reverse the process after drug removal, we may be able to exploit this phenomenon in the clinic," Nathanson said.
Co-authors of the study included Jonsson Cancer Center professors Harley Kornblum and James Heath (who also has an appointment at the California Institute of Technology) in collaboration with UCLA's Dr. Timothy Cloughesy and Nagesh Rao.
This is the first study to show reversible loss of an oncogene causing drug resistance, and it could hold promise for the treatment of other cancers susceptible to oncogene elimination, such as certain types of breast cancer.
This research was supported by the Ben and Catherine Ivy Foundation fund, the National Institutes of Health, the Ziering Family Foundation, the Art of the Brain fund, the James S. McDonnell Foundation, the European Commission, the Ruth L. Kirschstein Institutional National Research Service Award, the UCLA Scholars in Oncologic Molecular Imaging program and the Ludwig Institute for Cancer Research.
