Rewiring RNA: Antisense RNA Therapy Exposes a New Weakness in Pancreatic Cancer

Researchers at Cold Spring Harbor Laboratory identified an oncogenic SRSF1–AURKA–MYC circuit driving pancreatic ductal adenocarcinoma. Splice-switching antisense oligonucleotides targeting AURKA 5′ UTR alternative splicing collapsed the loop, reduced tumor cell viability, and triggered apoptosis. By simultaneously suppressing three key oncogenes, the RNA-based strategy reveals a potential therapeutic vulnerability beyond KRAS in one of oncology’s deadliest cancers with translational promise ahead.

Pancreatic ductal adenocarcinoma is the most common form of pancreatic cancer and the deadliest, with survival rates that have barely improved despite decades of effort. Much of that effort has focused on KRAS, the mutated oncogene that drives most PDAC tumors. Yet even as KRAS inhibitors move closer to the clinic, resistance continues to loom large, forcing researchers to look elsewhere for exploitable weaknesses.

A new line of work from Cold Spring Harbor Laboratory points to an unexpected vulnerability, not in a protein’s activity, but in how its RNA is assembled. By targeting a single splicing decision in a key cancer gene, researchers were able to collapse an entire oncogenic circuit that sustains aggressive pancreatic tumors.

The work builds on earlier discoveries from the laboratory of Professor Adrian Krainer, a pioneer in antisense oligonucleotide technology. In 2023, Krainer’s group showed that elevated levels of the splicing factor SRSF1 can jumpstart PDAC development. Revisiting those data, a team led by Alexander Kral realized that SRSF1 was not acting in isolation.

“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.”

At the center of this circuit is alternative splicing, the process by which cells assemble RNA transcripts in different ways to produce distinct outcomes. In PDAC cells, SRSF1 alters splicing in the 5′ untranslated region of AURKA, promoting the inclusion of an Alu derived exon. That change boosts AURKA mRNA accumulation and protein expression. Elevated AURKA, in turn, stabilizes the MYC protein and enhances SRSF1 levels through post-translational mechanisms. MYC then transcriptionally upregulates both SRSF1 and AURKA, completing a self-reinforcing 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.”

Disrupting that splicing decision became the team’s strategy. Using a splice-switching antisense oligonucleotide, or ASO, they targeted the AURKA 5′ UTR to prevent inclusion of the Alu-derived exon. The result was more than a partial hit on a single gene. In pancreatic cancer models, the ASO dismantled the entire SRSF1 AURKA MYC circuit, sharply reducing tumor cell viability and triggering 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 findings, detailed in a recent publication, frame AURKA alternative splicing as a critical regulatory node in pancreatic cancer. Importantly, the effects appear to be independent of AURKA’s kinase activity, which may help explain why conventional AURKA inhibitors have shown limited benefit in solid tumors. By contrast, the splice switching approach operates upstream, at the level of RNA processing, cutting off the oncogenic signal before it fully forms.

For Krainer’s lab, the strategy echoes a familiar trajectory. The group previously developed 'Spinraza', the first FDA approved antisense therapy for spinal muscular atrophy, by correcting a single splicing defect. That success demonstrated how precisely designed RNA therapies can translate from molecular insight to lifesaving medicine.