Short-circuiting pancreatic cancer: A potential RNA therapy

CSHL’s Krainer lab has discovered a key oncogenic circuit driving aggressive pancreatic ductal adenocarcinoma (PDAC) progression. Using human PDAC tumor organoids, seen here, the team developed a potential RNA splicing-based therapeutic that collapses the circuit. Credit: Krainer lab/CSHL

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal form of pancreas cancer. It’s also the most common form of the disease. Potential treatments typically target a key mutated oncogene called KRAS. In some cases, PDAC tumors with these mutations have resisted therapeutic efforts. However, combination therapies involving alternative drug targets may one day help clinicians overwhelm these defenses.

In 2023, Cold Spring Harbor Laboratory (CSHL) Professor Adrian Krainer’s lab discovered how the protein SRSF1 jumpstarts PDAC tumor development. Now, after revisiting data from that study, a team led by former CSHL graduate student Alexander Kral has found that SRSF1 doesn’t act alone. Instead, the protein is one of three pillars in a key circuit promoting aggressive PDAC progression.

The study is published in the journal Molecular Cell.

“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 explains. “We homed in on a molecule we thought could be an important driver of this called Aurora kinase A (AURKA). We found it’s part of a complex regulatory circuit that includes not only AURKA and SRSF1, but another key oncogene called MYC.”

In this circuit, SRSF1 regulates AURKA through a process called alternative splicing. This increases AURKA production, which allows it to stabilize and protect the MYC protein. MYC then increases SRSF1 levels, restarting the loop.

“Bits and pieces of this circuit were known previously, but we didn’t have the full picture until now,” Krainer says. “Once we figured out alternative splicing of AURKA was involved, we could start looking into ways to disrupt it.”

The team developed an antisense oligonucleotide (ASO) to alter the process. These molecules are a specialty of the Krainer lab. They previously developed an ASO called Spinraza, the first-ever FDA-approved treatment for spinal muscular atrophy.

Based on their observations, the team hoped their new ASO could obstruct AURKA’s alternative splicing. Remarkably, in pancreatic cancer, the ASO didn’t just interfere. It collapsed the entire oncogenic circuit. This reduced tumor cells’ overall viability and triggered a programmed cell death called apoptosis.

“It’s like killing three birds with one stone,” Krainer explains. “SRSF1, AURKA, and MYC are all oncogenes contributing to PDAC progression. Just by targeting AURKA splicing with our ASO, we see the loss of these other two molecules as well.

The Krainer lab is now working to refine their ASO. Potential clinical applications are still a long way off. However, Krainer says every clinical breakthrough begins with such basic research. That was true of Spinraza, which has saved thousands of lives. So, hopefully, it will be for the next lifesaving cancer treatment.

Examining a protein that contributes to pancreatic cancer