Commonly Mutated Gene Drives Cancer – Learning How To Correct It
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Genetic mutations are the spark and fuel for cancer. Hundreds of DNA mutations have been linked to human cancers, and they’re easier than ever to find and catalog, thanks to new genomic technologies.
But it’s remained difficult to find out what those mutations are doing to drive cancer growth so that scientists can design new treatments to intervene.
In new research published Wednesday in the journal Nature, a coast-to-coast group of collaborators applied a powerful new method to do just that. The team showed how one commonly mutated gene actually drives cancer growth and how, potentially, to counteract it.
“Even for very well-studied mutations, it’s frequently not obvious what the specific underlying processes are that promote cancer growth,” said the study’s co-leader, Dr. Robert Bradley of Fred Hutchinson Cancer Research Center in Seattle. “When we understand how to map a mutation to the development of cancer, then we can start to think about how to block that process for therapy.”
The gene Bradley and collaborators studied, called SF3B1, was mutated in 19 different ways in the several different cancer types they looked at. That gene is so critical to a fundamental cell process that when it is mutated, things get screwed up all over the cell.
The biggest surprise to the scientists was that, out of all this complexity, an elegantly simple answer emerged. No matter how SF3B1 was mutated, no matter in what type of cancer they examined, no matter what else was out of whack in the cells, just one key process was central in driving cancer growth.
(What was that process? More on that plot twist later.)
Once they knew what the problematic mechanism was, the scientists could intervene. In mice, implanted human tumors started to shrink when injected with the researchers’ custom-designed molecular repair kit.
Bradley and his collaborator, Dr. Omar Abdel-Wahab of New York City’s Memorial Sloan-Kettering Cancer Center, say that the experimental “treatment” they designed is years away from human patients.
For now, they hope their work prompts other researchers to study this mechanism to prove that it’s happening in many cancers with SF3B1 mutations, as Bradley and Abdel-Wahab’s work suggests. And, they hope, their results put groundwork in place for the eventual design of new targeted therapies that help real human patients with a variety of cancers.
“From a scientific perspective I think it's really exciting to be able to identify a direct connection between a specific genetic change that occurs in many cancers and the cancer phenotype [characteristics] itself,” Bradley said. “From a therapy perspective it's exciting because we were able to conduct proof of principle experiments in this paper to show that if we block that mechanism that we've identified, then we can slow or even prevent tumor growth, even once the tumors been established.”
CRISPR and Big Data: ‘Let the biology tell us the answer’
“If you look at this figure, it’s so obvious that it seems magical actually,” Bradley said, eyeing the graph. “You know, it’s not often, I feel like, in science that you do an experiment and it’s obvious. There was one result, and that is that.”
The simplicity of the answer prompted the scientists to go back and check their work. The raw data looked good. They repeated the test a few more times.
“It replicated really well,” Bradley said. “At that point I would say we started believing.”
“It was really black and white,” Abdel-Wahab said. “It doesn't matter which of those we look at, BRD9 is mis-spliced across any of those forms of cancer.”
Plot twist: ‘Junk DNA’ from ancient virus gets involved
Follow-up experiments confirmed the importance of that missing protein, BRD9, in the growth of several types of cancer cells, and mapped out the chain of events connecting SF3B1 to BRD9 to cancer development, maintenance and progression.
Then, another plot twist developed in the research.
No matter how SF3B1 was mutated, the scientists found it always screwed up the BRD9 protein in the exact same way: by failling to snip from its RNA code the fossil imprint of a dead virus that infected our primate ancestors millions of years ago. BRD9’s RNA codes turned out weird when they had the virus fossil in them, and the cells quickly broke them down — meaning that the BRD9 protein was not getting made.
Our genome is littered with such virus fossils. In fact, about 8% of the human genome can be traced back to now-extinct viruses that infected our ancestors sometime in the past 100 million years. Because some viruses reproduce by inserting their DNA into our genome to co-opt our normal processes of DNA replication, some of these sequences ended up getting passed down from parents to children and down through evolutionary history. The remnants of these sequences are part of what’s sometimes described as “junk DNA” in the human genome — not always an accurate descriptor, as scientists have identified important roles for some of this so-called junk in human health and disease.
Here, it turns out, is another.
“It's an interesting and odd observation that there's this piece of presumably junk DNA that appeared relatively recently in our genomes and that appears to be predisposing us to this kind of cancer,” Bradley said.
Odd though it might be, the fact that a single mechanism was so important to cancer growth provided the researchers with a clear opportunity to intervene. They designed tiny molecules that stuck to part of the virus fossil, preventing the spliceosome from pasting it into the instructions for making BRD9. Then, they tested the molecules in mice growing implanted human melanomas. The strategy worked: The problematic virus fossil stayed out of BRD9’s code, BRD9 was assembled correctly, and in both types of melanoma they examined, tumors grew more slowly and started to die.
“It’s striking to me that we could correct splicing of a single gene and slow tumor growth,” Bradley said. “Since hundreds of genes have errors in splicing in these cancers, I’d think it would be probably equally likely that you'd have to correct splicing of 50 of them to have any effect on the tumor.
“In fact, you can just hit one.”
Abdel-Wahab cautions that while the mechanism they identified “definitely seems to be a very big component of the disease process that just wasn’t realized,” he is certain scientists will identify other important cancer-driving mechanisms in patients with SF3B1 mutations. Cancer is too complicated for pat answers.
Could this become a cancer therapy?
As their experiments progressed, the researchers chose to focus in on two types of melanomas that affect parts of the eyes and the rectum. The choice was important to the team.
“We thought that we could have the biggest impact by focusing on an understudied cancer,” Bradley said. “If you can study a disease where other people haven't done as much previous work, you're most likely to make insights that will affect patients.”
The first-ever drug to correct aberrant RNA splicing was approved by the U.S. Food and Drug Administration in 2015 to treat people with a deadly, inherited muscle-wasting disease called spinal muscular atrophy. That drug is in the same family of molecule as the correctives that Bradley and Abdel-Wahab designed for their mice and, like theirs, it changes how the spliceosome prepares the instructions for making a certain protein.
“Now they have the first treatment for this really terrible disease, and it’s working,” Bradley said. “It’s already out there showing that this kind of thing can be translated” into a treatment for patients. He added: “It’s harder to do in cancer, probably. But it doesn’t mean it can’t be done.”
Now, he and Abdel-Wahab and colleagues hope to find collaborators who have the right expertise to develop their nascent experimental treatment strategy into a real therapy for people with SF3B1-mutated cancers.
“That is definitely the goal. We’d like it to affect patients,” Bradley said.
Reference: Inoue, et al. (2019) Spliceosomal disruption of the non-canonical BAF complex in cancer. Nature. DOI: https://doi.org/10.1038/s41586-019-1646-9
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