**Disrupting the Self-Sustaining Loop in Pancreatic Tumors**
Pancreatic tumors utilize a self-sustaining loop involving three cancer-promoting genes, creating a circuit that accelerates cell proliferation and resistance to treatment. Researchers at Cold Spring Harbor Laboratory have found a way to disrupt this mechanism by targeting the gene processing system instead of the genes.
The emphasis is on pancreatic ductal adenocarcinoma (PDAC), the deadliest variant of the illness. Past approaches aimed at the KRAS mutation have proven ineffective, leading the team to redirect their focus to the RNA splicing machinery critical for tumor progression.
**The Infinite Loop**
The oncogenes implicated in this loop are SRSF1, AURKA, and MYC. SRSF1, an RNA splicing factor, boosts the synthesis of Aurora kinase A (AURKA), which stabilizes the MYC gene, a key promoter of cell division. MYC subsequently raises SRSF1 levels, thus maintaining the cycle.
Alexander Kral, a scientist in Adrian Krainer’s laboratory, recognized this trend and linked it to heightened tumor development. The significant finding was the involvement of AURKA’s alternative splicing, uncovering a new pathway for intervention.
To break the loop, the researchers designed an antisense oligonucleotide (ASO) to inhibit AURKA splicing. This strategy builds on prior achievements, including the creation of Spinraza for spinal muscular atrophy.
In human pancreatic tumor organoids, this ASO obstructed the cancer circuit, decreasing cell viability and inducing apoptosis.
**An Evolutionary Genetic Oddity**
The target area for the ASO originates from Alu elements, DNA sequences specific to primates. While typically overlooked in healthy cells, in cancer, SRSF1 compels their incorporation, thus promoting tumor development.
Though clinical implementation lies ahead, this research hints at a fundamental change in the approach to treating pancreatic cancer—focusing on dismantling the mechanisms that sustain tumors instead of targeting discrete mutations.
Krainer’s team draws comparisons to their efforts on Spinraza, hoping this approach will similarly transform treatment for a particularly resistant form of cancer.
For further information on the research, see [Molecular Cell: 10.1016/j.molcel.2025.12.004](https://doi.org/10.1016/j.molcel.2025.12.004).