Unraveling the paradoxical relationship between epigenetic regulation and cancer progression
Imagine a silent predator that strikes with little warning, evades detection, and resists nearly every treatment thrown its way. This isn't a creature from science fiction—it's the reality of pancreatic cancer, one of medicine's most formidable foes.
Five-year survival rate
Annual diagnoses in the U.S.
Cases with KRAS mutations
With a dismal 9% five-year survival rate that has barely budged in decades, pancreatic cancer ranks among the deadliest of all cancers8 . Each year, approximately 60,430 people in the United States receive this devastating diagnosis, and about 48,220 will die from the disease2 8 .
But what makes this cancer so relentless? The answer lies in its molecular machinery, particularly in a genetic bully known as KRAS—a mutated gene that drives about 85% of pancreatic cancers8 . For decades, researchers have struggled to tame KRAS, but recent discoveries have revealed an unexpected accomplice: KDM5A, an epigenetic regulator that appears to support KRAS-driven tumors in ways nobody anticipated. The most surprising revelation? Sometimes losing KDM5A makes the cancer even more aggressive, flipping conventional wisdom on its head.
This article will take you inside the laboratory where scientists are unraveling these molecular mysteries, exploring how the relationship between KRAS and KDM5A could hold the key to revolutionizing pancreatic cancer treatment. What they're discovering might just change the future for patients facing this daunting diagnosis.
To understand pancreatic cancer, you must first meet KRAS—a critical signaling molecule that normally acts as a carefully controlled switch within cells, regulating growth and division. But in pancreatic cancer, this switch gets stuck permanently in the "on" position8 .
Think of KRAS as the ignition system of a car—when working properly, it allows the engine to start and run smoothly. In pancreatic cancer, however, the ignition gets jammed, causing the engine to rev uncontrollably until it ultimately destroys itself—and the vehicle along with it.
If KRAS is the stuck ignition, then KDM5A belongs to the team of mechanics that determine how the engine responds to this problem. KDM5A is part of the KDM5 family of histone demethylases—specialized proteins that act as epigenetic regulators that influence how genes are read without changing the DNA sequence itself2 .
Think of our DNA as a vast library containing all the information needed to run a cell. Epigenetic regulators like KDM5A act as librarians who determine which books are accessible and which remain shelved.
Specifically, KDM5A removes chemical tags (methyl groups) from histones—the spools around which DNA winds—effectively changing how tightly packed DNA is and whether specific genes can be activated2 . Under normal circumstances, this helps fine-tune gene expression patterns. But in cancer, KDM5A often goes awry, with research showing it becomes significantly overexpressed in many tumor types, including pancreatic cancer2 .
For years, scientists assumed KDM5A primarily supported cancer by silencing tumor-suppressor genes. But recent research has revealed a more complex story—especially in pancreatic cancer. Studies indicate that KDM5 family members frequently interact with other key cancer drivers, including proteins in the notorious Ras signaling pathways2 . Even more intriguingly, KDM5 proteins show strong interactions with histone deacetylases (HDACs)—another class of epigenetic regulators—suggesting they work together in molecular teams that shape the cancer cell's behavior2 .
The relationship between KRAS and KDM5A represents a fascinating molecular partnership—the stuck ignition system and the epigenetic tuner working in concert to drive cancer progression. But what happens when you remove one of these partners? The answers, as we'll see, are counterintuitive.
To investigate the paradoxical relationship between KDM5A loss and KRAS-driven pancreatic cancer, researchers designed a comprehensive study using genetically engineered mouse models that replicate human pancreatic cancer. These specialized laboratory mice carry the same KRAS mutations found in human patients, allowing scientists to track how the disease develops and progresses in a controlled setting.
The research team used advanced genetic techniques to selectively disable the KDM5A gene in mice that already had KRAS-driven pancreatic tumors. This approach allowed them to observe precisely what happens when pancreatic cancer cells lose KDM5A while maintaining hyperactive KRAS signaling. They monitored tumor development, progression, and spread, comparing results between mice with functional KDM5A and those without it.
Creation of genetically engineered mouse models with KRAS mutations
Selective disabling of KDM5A in KRAS-mutant pancreatic tumors
Observation of tumor development, progression, and metastasis
Comparison between KDM5A-functional and KDM5A-deficient models
At the molecular level, the scientists employed cutting-edge methods to unravel how KDM5A loss impacts pancreatic cancer cells:
Examining which genes were turned on or off after KDM5A removal
Mapping epigenetic changes across the genome
Using human pancreatic cancer cells to validate findings
Observing changes in cell behavior and characteristics
This multi-faceted approach allowed the team to connect molecular changes with actual cancer behaviors, creating a comprehensive picture of how KDM5A influences KRAS-driven tumor development.
The results of this investigation revealed several surprising patterns that challenge conventional thinking about cancer epigenetics. The relationship between KDM5A and KRAS-driven pancreatic cancer proved far more complex than simple linear models would predict.
| Aspect Measured | Effect of KDM5A Loss | Scientific Significance |
|---|---|---|
| Tumor growth rate | Significant acceleration | Challenges view that KDM5A always promotes cancer |
| Tumor spread | Increased metastasis | Suggests KDM5A normally restricts migration |
| Cellular features | Enhanced stem-like properties | Indicates shift to more primitive, aggressive state |
| Therapeutic resistance | Increased chemotherapy resistance | Reveals complication for treatment |
Perhaps the most counterintuitive finding was that KDM5A loss accelerated tumor growth and made cancers more likely to spread. This directly contradicts the typical expectation that genes overexpressed in cancer are always promoting the disease. Instead, KDM5A appears to play a context-dependent role—sometimes supporting cancer, but in specific situations actually restraining it.
The pancreatic cancer cells lacking KDM5A developed enhanced stem cell-like properties, making them more primitive, flexible, and dangerous. These "de-differentiated" cells represent a more aggressive form of cancer that typically resists conventional therapies and seeds new tumors throughout the body.
Molecular analysis revealed that KDM5A removal triggered significant changes in which genes were active in cancer cells. Specifically, researchers observed:
| Gene Category | Direction of Change | Functional Consequences |
|---|---|---|
| Developmental genes | Upregulated | Enhanced stem-like properties |
| Differentiation markers | Downregulated | Loss of specialized features |
| Metabolic pathway genes | Varied | Rewired energy production |
| Cell migration genes | Upregulated | Increased invasive potential |
The discovery that KDM5A loss can accelerate KRAS-driven pancreatic cancer has profound implications for treatment development. Rather than simply inhibiting KDM5A activity—an approach that might backfire in some patients—researchers now recognize the need for more nuanced strategies. These might include:
Targeting both KRAS signaling and specific epigenetic pathways simultaneously
Identifying which patients would benefit from KDM5A inhibition versus other treatments
Developing regimens that account for the complex role of epigenetic regulators
The research also highlights why many targeted therapies fail in clinical trials—cancer biology often proves more complicated than initial models suggest. The relationship between KRAS and KDM5A exemplifies the adaptive resilience of cancer cells, which can sometimes turn attempted treatments to their advantage.
These findings about KDM5A align with broader patterns emerging in pancreatic cancer research. The KDM5 family more broadly—including KDM5B and KDM5C—has been implicated in multiple aspects of tumor biology, from therapy resistance to immune system evasion2 . Additionally, the interconnected nature of epigenetic regulators suggests that targeting entire networks rather than individual components might yield better results.
Despite the challenges, there are genuine reasons for optimism. The growing understanding of KRAS and its epigenetic partners comes at a time of unprecedented progress in pancreatic cancer research. Recent clinical trials presented at the 2025 ASCO Annual Meeting demonstrated that:
As Dr. Anna Berkenblit noted in her ASCO 2025 research spotlight, "Progress is happening. New treatments are pushing the boundaries of what is possible"9 .
The discovery that KDM5A loss can support KRAS-driven pancreatic cancer represents both a challenge and an opportunity. It reveals another layer of complexity in this formidable disease while simultaneously providing new avenues for intervention. Rather than discouraging researchers, these findings highlight the importance of understanding context in cancer biology and developing therapies that account for this complexity.
For patients and families facing pancreatic cancer, this ongoing research offers something crucial: hope through advancing knowledge. Each discovery, each paradoxical finding, and each failed hypothesis brings us closer to unraveling pancreatic cancer's secrets. The path forward will require continued investment, creative thinking, and collaboration across scientific disciplines—but the destination is worth the journey.
As this research progresses, it reinforces a fundamental truth: in the fight against pancreatic cancer, knowledge isn't just power—it's potential life saved. And with each new discovery, we add another weapon to our arsenal against this formidable disease.
To learn more about pancreatic cancer research or find support resources, visit the Pancreatic Cancer Action Network at pancan.org9 .