Scientists at Università Cattolica reported on the discovery of a genetic mechanism that pancreatic cancer cells employ to evade treatment, and which the investigators say could pave the way to the development of new anticancer drugs. Their study, including experiments in pancreatic cancer cell lines and patient-derived organoids, identified a splicing signature that was associated with molecularly and clinically distinct pancreatic adenocarcinoma (PDAC) subtypes, and also identified the splicing factor Quaking (QKI), as a marker of basal-like PDAC that is more likely to be associated with chemoresistance.
“We have discovered a mechanism based on the regulation of messenger RNAs that contributes to chemotherapy resistance,” explained research lead Claudio Sette, PhD, professor of human anatomy at the Catholic University, and director of the organoids facility at the Policlinico Universitario A. Gemelli IRCCS. “Our discovery opens up new treatment possibilities for a type of tumor that generally does not respond to existing therapies.”
Sette and colleagues reported on their findings in Cell Reports Medicine, in a paper titled, “An alternative splicing signature defines the basal-like phenotype and predicts worse clinical outcome in pancreatic cancer.” In their paper the team concluded, “These findings reveal that QKI is a reliable basal-like marker and defines a subtype-specific splicing signature with prognostic potential in PDAC, which may allow more precise stratification of patients for the selection of the available clinical options.”
Pancreatic cancer affects approximately 500,000 people worldwide each year. Despite being the 14th most common cancer by incidence, today it is the seventh leading cause of cancer-related death. The five-year survival rate is less than 10%, mostly limited to patients who are eligible for surgery (around 20–30% of the total).
Prior work has identified two main molecular PDAC subtypes, classical and basal-like. “Transcriptomic analyses revealed the existence of classical and basal-like phenotypes, which differ in their responses to current therapies and clinical course,” the scientists explained. Compared with the classical subtype, basal-like PDAC is associated with worse chemotherapy response and prognosis. “PDAC presents with molecularly distinct subtypes, with the basal-like one being associated with enhanced chemoresistance,” they added. “Thus, identification of molecular features that distinguish tumors with different clinical course is of paramount importance to improve management of patients with PDAC and particularly of unresectable cases that face different clinical options.”
When the genetic code is transcribed into RNA for protein synthesis, alternative splicing can lead to the production of different transcripts from the same gene, depending on the selected genetic “cards,” or exons—the gene’s coding part for amino acids in proteins—that are “played.” Splicing leads to the production of diverse proteins with different roles through the alternative assortment of exons of the original gene. Splicing is generally altered in tumors, including pancreatic cancer, but as the authors noted, while splicing dysregulation contributes to PDAC, “… its involvement in subtype specification remains elusive.”
The newly reported research by Sette and colleagues has now identified a subtype-specific splicing signature associated with prognosis in PDAC. Their research further identified the splicing factor QKI as a determinant of that basal-like signature.
“Comparing pancreatic tumors of different subtypes,” Sette explained, “we observed that the therapy-resistant cancer is associated with a specific splicing regulation, leading to the synthesis of proteins associated with resistance to chemotherapies. Our study also identified a splicing regulator called Quaking that is expressed in more aggressive pancreatic tumors and promotes the synthesis of proteins conferring chemoresistance.” The team added, “Furthermore, the subtype-specific splicing events identified in our study are strongly correlated with a patient’s survival.”
The authors say that their results, together with recent studies highlighting the contribution of other splicing factors to PDAC onset, chemotherapy resistance, and metastasis, point to splicing dysregulation as a crucial process during pancreatic tumorigenesis. “They also suggest that QKI is a valuable target to counteract PDAC malignancy,” the investigators noted.
Existing splicing-regulating drugs could be potentially employed for this type of cancer; including therapies for individual splicing events, such as the drug nusinersen that is currently used in spinal muscular atrophy. “There are already RNA-targeting drugs, used with other medical indications, to counteract this type of regulation,” Sette said. “These drugs could potentially be developed as anti-tumor agents for resistant patients.”
Acknowledging limitations of their study, the authors further noted, “Given the fast-growing development of RNA-based therapies, it is conceivable that targeting the splicing program orchestrated by QKI in PDAC cells might be exploited to limit their plasticity and to freeze them into a state that is more susceptible to chemotherapy.”
