A recent study revealed a hidden three-part molecular loop aggressively fueling deadly pancreatic cancer, offering a new therapeutic target beyond conventional methods. Researchers at Cold Spring Harbor Laboratory identified this self-reinforcing circuit involving oncogenes SRSF1, AURKA, and MYC. This critical discovery, reported on ScienceDaily in January 2026, provides hope for more effective treatments against pancreatic ductal adenocarcinoma (PDAC).
Pancreatic cancer, particularly PDAC, remains one of the most challenging malignancies to treat, often developing resistance to existing therapies. Many current strategies focus on blocking the frequently mutated KRAS gene, which, while effective in some cases, often sees tumors evading these interventions.
The persistent challenge of treatment resistance has driven scientists to explore additional molecular targets. Understanding complex interactions within cancer cells is paramount to developing combination therapies that can overcome this formidable disease.
Unraveling the oncogenic circuit
In 2023, Professor Adrian Krainer’s lab at CSHL first identified SRSF1 as an early trigger for PDAC tumor formation. Building on this, former CSHL graduate student Alexander Kral led a new team, realizing SRSF1 was not isolated but part of a complex system. “Our theory was that some of the changes caused by increased levels of SRSF1 were playing a role in the accelerated tumor growth we were seeing,” Kral explained.
The team pinpointed Aurora kinase A (AURKA) as a critical driver within this system. They discovered an intricate regulatory circuit encompassing SRSF1, AURKA, and another key oncogene, MYC. This self-reinforcing pancreatic cancer loop functions by SRSF1 controlling AURKA through alternative splicing, leading to higher AURKA levels.
Elevated AURKA then stabilizes and protects the MYC protein, which in turn boosts the production of SRSF1, restarting the cycle. This continuous feedback loop allows the cancer to proliferate aggressively. Krainer noted, “Bits and pieces of this circuit were known previously, but we didn’t have the full picture until now.”
Collapsing the loop with targeted therapy
With a comprehensive understanding of the circuit, the research team sought ways to disrupt it. They developed an antisense oligonucleotide (ASO) specifically designed to alter how AURKA is spliced. ASOs are short synthetic molecules, a field where the Krainer lab has significant expertise, having previously developed Spinraza for spinal muscular atrophy.
Unexpectedly, the ASO treatment in pancreatic cancer cells yielded a far more dramatic outcome than merely blocking AURKA splicing. It caused the entire three-part cancer-driving circuit—SRSF1, AURKA, and MYC—to collapse completely. This led to a significant loss of tumor cell viability and triggered apoptosis, programmed cell death.
“It’s like killing three birds with one stone,” Krainer stated, emphasizing the simultaneous loss of all three oncogenes by targeting just AURKA splicing. This single-target approach offers immense potential for future therapies, proving that disrupting one component can dismantle the entire oncogenic network.
While the ASO is still in refinement and its clinical application is distant, this foundational research marks a pivotal step in the fight against pancreatic cancer. The ability to collapse a critical oncogenic circuit with a single targeted molecule opens new avenues for developing smarter, more effective treatments. Such breakthroughs underscore the importance of deep molecular understanding in transforming patient outcomes.
