Exploring Splicing Modulation as an Innovative Approach to Combat Pancreatic Cancer: SF3B1 Emerges as a Prognostic Indicator and Therapeutic Target

• Published in: International journal of biological sciences Vol. 20; no. 8; pp. 3173 - 3184
• Main Authors: Sciarrillo, Rocco, Terrana, Francesca, Comandatore, Annalisa, Supadmanaba, I Gede Putu, Wang, Bing, Hassouni, Btissame El, Mantini, Giulia, Jansen, Gerrit, Avan, Amir, Carbone, Daniela, Diana, Patrizia, Peters, Godefridus J, Morelli, Luca, Cloos, Jacqueline, Assaraf, Yehuda G, Giovannetti, Elisa
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher 01.01.2024
• Subjects: Alternative Splicing; Animals; Apoptosis - drug effects; Apoptosis - genetics; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor; Cell Movement - genetics; Epoxy Compounds - pharmacology; Epoxy Compounds - therapeutic use; Female; Humans; Macrolides - pharmacology; Macrolides - therapeutic use; Mice; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Phosphoproteins - genetics; Phosphoproteins - metabolism; Prognosis; Research Paper; RNA Splicing; RNA Splicing Factors - genetics; RNA Splicing Factors - metabolism; E7107; PDAC; splicing; SF3B1 modulators; SF3B1; Pladienolide-B
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.92671

Pancreatic ductal adenocarcinoma (PDAC) poses significant challenges in terms of prognosis and treatment. Recent research has identified splicing deregulation as a new cancer hallmark. Herein, we investigated the largely uncharacterized alternative splicing profile and the key splicing factor SF3B1 in PDAC pancreatic cells and tissues as a potential discovery source of plausible drug targets and new predictive biomarkers of clinical outcome. The research involved a transcriptome-wide analysis, comparing profiles of splicing profiles in PDAC primary cells with normal ductal cells. This revealed more than 400 significant differential splicing events in genes involved in regulation of gene expression, primarily related to mRNA splicing, and metabolism of nucleic acids. PDAC cultures were highly sensitive to the SF3B1 modulators, E7107 and Pladienolide-B, showing IC50s in the low nanomolar range. These compounds induced apoptosis, associated to induction of the MCL-1/S splice variant. and reduced cell migration, associated to RON mis-splicing. In an orthotopic mouse model, E7107 showed promising results. Furthermore, we evaluated SF3B1 expression in specimens from 87 patients and found a significant association of SF3B1 expression with progression-free and overall survival. In conclusion, SF3B1 emerges as both a potential prognostic factor and therapeutic target in PDAC, impacting cell proliferation, migration, and apoptosis. These findings warrant future studies on this new therapeutic strategy against PDAC.