Researchers at Cold Spring Harbor Laboratory (CSHL) have identified a three-component oncogenic regulatory circuit contributing to the progression of pancreatic ductal adenocarcinoma (PDAC), the most lethal and prevalent form of pancreas cancer. This circuit involves the proteins SRSF1, Aurora kinase A (AURKA), and the oncogene MYC. The team subsequently developed an antisense oligonucleotide (ASO) designed to disrupt this circuit by targeting AURKA's alternative splicing, demonstrating a reduction in tumor cell viability and induction of programmed cell death in preclinical models.
Pancreatic Ductal Adenocarcinoma Challenges
Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal and prevalent form of pancreas cancer. Existing therapeutic approaches often target the mutated oncogene KRAS, but some PDAC tumors carrying these mutations have shown resistance to current treatments. This resistance highlights the need for alternative therapeutic strategies and drug targets.
Discovery of a Key Oncogenic Circuit
In 2023, Professor Adrian Krainer's laboratory at CSHL identified the protein SRSF1 as a factor in PDAC tumor development. Subsequent analysis, led by former CSHL graduate student Alexander Kral, elucidated a three-component regulatory circuit involving SRSF1, Aurora kinase A (AURKA), and the oncogene MYC. While various aspects of these interactions were known, the complete regulatory circuit was fully defined through this research. This circuit is understood to promote PDAC progression.
Mechanism of the Circuit
Within the identified circuit, the following interactions occur:
- SRSF1 regulates AURKA through alternative splicing, leading to increased production of AURKA.
- Elevated AURKA levels then stabilize and protect the MYC protein.
- MYC, in turn, contributes to increased SRSF1 levels, thereby perpetuating the loop.
Therapeutic Intervention
The research team developed an antisense oligonucleotide (ASO) specifically designed to modify AURKA's alternative splicing. ASOs are a focus area for the Krainer lab, which previously developed Spinraza, an FDA-approved treatment for spinal muscular atrophy.
In preclinical pancreatic cancer models, this ASO successfully disrupted AURKA's alternative splicing. This disruption led to the collapse of the entire SRSF1-AURKA-MYC oncogenic circuit, impacting SRSF1 and MYC levels. The intervention resulted in a reduction of tumor cell viability and induced programmed cell death, known as apoptosis.
Future Outlook
The Krainer laboratory is currently engaged in refining the developed ASO. Researchers state that clinical applications for this specific treatment are considered to be a long-term development. The study highlights the role of foundational basic research in paving the way for potential clinical advancements.