By knocking out a protein duo’s “bodyguard” role, researchers have exposed a hidden weakness in pancreatic cancer. It’s a discovery that could lead to smarter, more effective treatments for one of the deadliest cancers.
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. With an overall survival rate of around 13%, it’s also one of the deadliest cancers. One reason for this is that the cancer is intrinsically resistant to nearly all forms of treatment, including chemotherapy, radiotherapy, and immunotherapy.
Now, though, a new study led by researchers from Indiana University’s (IU) School of Medicine has identified a way to weaken PDAC’s built-in defenses, offering a more effective treatment strategy for it and, potentially, other aggressive cancers.
“This research shows us a brand new vulnerability in pancreatic cancer,” said Melissa Fishel, PhD, study co-author and tumor cell biologist at the IU School of Medicine. “That opens the door to developing combination therapies that could work better than anything currently available, not just for pancreatic cancer but potentially for other aggressive cancers too.”
The researchers focused on two proteins they already knew were implicated in PDAC: redox effector factor-1 (Ref-1) and peroxiredoxin-1 (PRDX1). Both are abnormally abundant in pancreatic tumors compared with normal tissue and they work hand-in-hand to create resistance to treatment in pancreatic cancer cells. By studying Ref-1 and PRDX1 together, the researchers wanted to see if they could exploit this partnership, turning it into a therapeutic weakness.
Think of Ref-1 like a switchboard operator for cancer genes. Many cancer-driving transcription factors, which are proteins that bind to specific DNA sequences to control gene activity, need to be in the right chemical (redox) state to work. Ref-1 keeps them switched on, so they can turn up the activity of genes that help cancer cells grow, resist stress, and avoid dying. PRDX1 is, essentially, Ref-1’s bodyguard. Its main job is to clean up harmful molecules called reactive oxygen species (ROS), which build up in cells. By controlling the cell’s redox balance, PRDX1 makes sure Ref-1 can keep doing its job of activating cancer-driving genes. This “protection service” makes cancer cells tougher, because Ref-1 and its partners can keep the tumor alive even under stress.
The researchers used CRISPR/Cas9 gene editing and small interfering RNA (siRNA) to reduce or “knock down” the expression of PRDX1 from pancreatic cancer cells. The cells were then treated with a drug, APX2014, that blocks Ref-1’s redox activity. This approach was tested using cell cultures (tumor cells and cancer-associated fibroblasts (CAFs), a central component of the tumor microenvironment), 3D co-culture models (that better mimic the tumor environment), and mice implanted with human tumor cells (xenografts). Assays and tests were conducted to check cell viability, apoptosis (programmed cell death), transcription factor activity, gene expression, protein levels, and survival in mice.
A brief aside is necessary to discuss CAFs in more detail, as they will be featured in the next section. In tumors, the stroma is the supporting tissue that surrounds cancer cells. It includes immune cells, blood vessels, and extracellular matrix, or the scaffolding around cells. In PDAC, one particular type of stromal cell, CAFs, dominates the stroma, creating a physical barrier that makes it hard for drugs and immune cells to penetrate the tumor. CAFs aren’t passive, though. They communicate with tumor cells by releasing growth factors, inflammatory signals, and remodeling the tissue around them, all of which helps the cancer cells resist stress, grow faster, and spread.
When Ref-1 was inhibited, the researchers found that PRDX1 was critical for cancer survival. Removing PRDX1 made the pancreatic cancer cells much more sensitive to the Ref-1-blocking drug, APX2014. Other peroxiredoxins didn’t have this effect. The removal of PRDX1 in combination with APX2014 treatment also caused strong apoptosis. In the co-culture models with CAFs, this combination disrupted the survival of both the tumor cells and stromal cells. Unexpectedly, the study showed that CAFs rely on redox proteins like PRDX1 and Ref-1, meaning that the tumor and its stroma are in a chemical partnership, keeping each other alive in the harsh environment of pancreatic cancer.
Mice implanted with PRDX1-knockout tumors and treated with APX2014 had smaller, lighter tumors, lower Ref-1, and improved survival. In human tissues, patient tumor samples showed higher levels of both Ref-1 and PRDX1 compared to normal tissues, confirming their clinical relevance.
“What really surprised us was how specific PRDX1 was in driving this effect,” said Mark Kelley, PhD, corresponding author and a professor of pediatric cancer research at the IU School of Medicine. “Among the entire family of related proteins, only loss of PRDX1 made tumors so much more sensitive to our Ref-1 drug. The combination worked better than either treatment alone, and in animal models, it resulted in smaller tumors and longer survival.”
The study had limitations. Most data are from lab-grown cells and mouse models; human trials are needed. The drug APX2014 was injected directly into tumors in mice, whereas clinical use would rely on oral or intravenous delivery, which may behave differently. While PRDX1 depletion weakened CAFs, the exact tumor-stroma redox interactions remain poorly understood and may limit predictability.
These limitations are important, however, the research suggests that dual targeting of Ref-1 and PRDX1 could overcome drug resistance in pancreatic cancer treatment, offering a new therapeutic angle. And, because other cancers rely on oxidative/redox signaling, this dual-targeting approach could extend beyond pancreatic cancer to other forms of aggressive cancer.
While APX2014 was injected into mouse tumors, its close relative, APX3330, is already available as an oral drug and is being tested in human trials. This raises the possibility of shortened translation – that is, moving from lab and animal research into treatments that can be tested in people – once PRDX1 inhibitors have been developed.
The study was published in the journal Redox Biology.
