Beating drug resistance
By Chonglu Huang
Resistance to drug treatment is a major obstacle to curing many cancers.
Time and again, scientists have seen chemotherapeutics wipe out almost all of the cancer cells in a patient, but then the cancer comes back.
That’s often because some cells have developed drug resistance due to genetic changes that frequently occur in cancer. However, new research at the University of Ottawa’s Faculty of Medicine may point to ways of tempering this genetic change, thus increasing the chance of eliminating cancer cells.
“A tumour is essentially evolution happening continuously through competition between cancer cells, with tens to hundreds of genetic mutations that cause cancer and then make it more aggressive,” says Dr. Derrick Gibbings, assistant professor in the Faculty of Medicine’s Department of Cellular and Molecular Medicine. Gibbings led this research project, whose findings were recently published in Nature Communications.
A major source of genetic mutation is retrotransposons, or “jumping genes,” which are genetic elements that can copy and paste themselves into new positions within the genome, creating mutations and altering the cell’s genome size. In fact, retrotransposons account for a large proportion of the genetic differences between people as well as between humans and other species.
“Retrotransposons are essentially these ancient viruses that inhabit our genome and those of all other animals,” says Gibbings. “Everyone is born with millions of copies of these viruses in their genome that their parents and ancestors acquired before them. What we’ve recently learned is that these ancient viruses are actively replicating themselves and reinserting into the genome throughout our lifetimes.”
This kind of genetic behaviour is a key component of human evolution and our survival as a species. At the same time, it leads to cell mutations that can give rise to cancerous tumour clones that are aggressive, metastatic and resistant to chemotherapeutics.
Gibbings and his team have identified a mechanism that degrades retrotransposons as they try to replicate and prevents new retrotransposon mutations of the genome. This mechanism is a normal physiological process that deals with destruction of old and bad parts of cells known as autophagy. Notably, in 35% to 70% of ovarian and breast tumours, genes essential for autophagy are inactive.
“This suggests that in a major proportion of these cancers, where autophagy is not working effectively, retrotransposons are freed to mutate the genome and this may cause the emergence of tumours, or their ability to spread and evolve drug resistance,” explains Gibbings.
Indeed, Gibbings’ current research further shows that tumours from human patients with decreased autophagy genes have increased levels of retrotransposon RNA.
“This finding has all kinds of real medical implications,” he says.
Most significant is that clinically proven drugs that can activate autophagy may be able to limit retrotransposons from causing genetic mutation, tumours and drug resistance. Drugs that can slow the emergence of resistance to chemotherapeutics have the potential to address many major obstacles in cancer treatment.
“This research publication is one of the first to explore a broad new class of substrates degraded by autophagy, namely RNA, that had previously been mostly ignored,” says Gibbings. He added that one of his research team’s broader goals now is to explore RNA degradation further and what it means for disease.
“I find retrotransposons fascinating because they are both enemies and friends that we’ve lived with for millions of years,” says Gibbings. “On one hand, they’re a pathogen that causes diseases, but on the other hand, they’ve done a lot of good things for us — they have allowed us to take genes necessary for the placenta to form and they’ve helped us in the evolution of the immune system. In essence, this means humans would not exist without retrotransposons – something that shapes and tempers who we are.”
Dr. Derrick Gibbings, assistant professor in the Faculty of Medicine’s Department of Cellular and Molecular Medicine, working in his laboratory.