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Exploring Splicing Modulation as an Innovative Approach to Combat Pancreatic Cancer: SF3B1 Emerges as a Prognostic
Rocco Sciarrillo1,2,3, Francesca Terrana1,4, Annalisa Comandatore1,5
1Department of Medical Oncology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
Abstract:
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.
Insights
Pancreatic cancer (PDAC) shows altered splicing. Targeting SF3B1 with drugs like E7107 effectively reduced cancer cell growth and migration, offering a new therapeutic strategy and biomarker.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Pancreatic ductal adenocarcinoma (PDAC) presents significant treatment challenges.
- Splicing deregulation is recognized as a key hallmark of cancer.
- The role of the splicing factor SF3B1 in PDAC remains largely uncharacterized.
Purpose of the Study:
- To investigate the alternative splicing profile in PDAC.
- To evaluate SF3B1 as a potential therapeutic target and biomarker in PDAC.
- To identify novel drug targets and predictive biomarkers for PDAC clinical outcome.
Main Methods:
- Transcriptome-wide analysis comparing splicing profiles in PDAC cells and normal ductal cells.
- Assessment of PDAC cell sensitivity to SF3B1 modulators (E7107, Pladienolide-B).
- Evaluation of SF3B1 expression in patient specimens (n=87) and correlation with survival outcomes.
Main Results:
- Over 400 differential splicing events identified in PDAC, affecting gene expression regulation, mRNA splicing, and nucleic acid metabolism.
- PDAC cells exhibited high sensitivity to SF3B1 modulators, with low nanomolar IC50 values.
- SF3B1 modulators induced apoptosis (via MCL-1/S variant) and reduced cell migration (via RON mis-splicing).
- E7107 demonstrated promising efficacy in an orthotopic mouse model.
- Higher SF3B1 expression correlated significantly with improved progression-free and overall survival in PDAC patients.
Conclusions:
- SF3B1 is a critical factor in PDAC, influencing proliferation, migration, and apoptosis.
- SF3B1 represents a promising therapeutic target and prognostic biomarker for PDAC.
- Targeting SF3B1 warrants further investigation as a novel therapeutic strategy for PDAC.
