Here’s a startling fact: triple-negative breast cancer, one of the deadliest forms of the disease, currently has no targeted therapies available. But a groundbreaking discovery from Purdue University might just change that. Led by Kyle Cottrell, a team of researchers has uncovered a new therapeutic target that could revolutionize treatment for this aggressive cancer.
In a study published in the journal RNA, Cottrell, biochemistry graduate student Addison Young, and their colleagues shed light on the role of double-stranded ribonucleic acid (dsRNA)-binding proteins. And this is the part most people miss: while high school biology teaches us that RNA is single-stranded, human cells—and viruses—actually contain many double-stranded segments of RNA. These dsRNA molecules are recognized by specific proteins, triggering pathways that typically fight viral infections. But here’s where it gets controversial: when these pathways are activated without a viral threat, they can cause problems like inflammation and have even been linked to aging and neurodegenerative disorders.
Cottrell explains, ‘As you age, your cells lose the ability to block these sensing pathways, leading to chronic inflammation.’ This phenomenon, known as viral mimicry, has sparked interest in how dsRNA-binding proteins might play a role in cancer. For instance, some cancer immunotherapies work better when cells mimic a viral infection, creating a unique cellular state that enhances treatment efficacy.
The Purdue team focused on a dsRNA-binding protein called PACT (protein activator of interferon-induced protein kinase). Their research, along with studies from two other groups, reveals that PACT suppresses another protein, PKR (RNA-activated protein kinase). This finding settles a long-standing debate: ‘Our evidence firmly establishes PACT as a suppressor, not an activator, of PKR,’ Cottrell notes. This clarity is crucial, as it identifies PACT as a potential therapeutic target for triple-negative breast cancer.
But why does this matter? PKR is a key sensor of double-stranded RNA, alerting cells to viral infections. By suppressing PKR, PACT could inadvertently allow cancer cells to thrive. Cottrell’s team used CRISPR-Cas9 gene editing to remove PACT from cells, observing which pathways were affected. They found that triple-negative breast cancer cells are particularly sensitive to PACT depletion, making it a promising target for new therapies.
However, PACT isn’t an enzyme, so traditional drug design methods won’t work. Instead, researchers must find a way to block its dimerization—the process where two PACT molecules fuse to become functional. ‘If we can prevent dimerization, we can inhibit PACT’s function,’ Cottrell explains. This approach could lead to targeted therapies that spare healthy cells, unlike chemotherapy, which often causes severe side effects.
The study also raises thought-provoking questions: How do cells prevent the overactivation of dsRNA sensors like PKR? And could targeting PACT dimerization be the key to treating not just breast cancer, but other diseases linked to dsRNA pathways? Cottrell’s team is already working on these challenges, aiming to develop a molecule that inhibits PACT dimerization.
This research is part of Purdue’s One Health initiative, which integrates human, animal, and plant health studies. Supported by grants from the Ralph W. and Grace M. Showalter Research Trust Award, the National Institutes of Health, and others, this work exemplifies Purdue’s commitment to tackling complex health issues.
So, what do you think? Could targeting PACT dimerization be the next big leap in cancer treatment? Or are there potential risks we’re not considering? Share your thoughts in the comments—let’s spark a conversation about the future of cancer therapy.
