Dysregulated splicing factor SF3B1 unveils a dual therapeutic vulnerability to target pancreatic cancer cells and cancer stem cells with an anti-splicing drug
Emilia Alors‐Pérez, Ricardo Blázquez‐Encinas, Sonia Alcalá, Cristina Viyuela-García, Sergio Pedraza‐Arévalo, Vicente Herrero‐Aguayo, Juan M. Jiménez‐Vacas, Andrea Mafficini, Marina Sánchez‐Frías, María Teresa Cano, Fernando Abollo‐Jiménez, Juan Antonio Marín-Sanz, Pablo Cabezas‐Sainz, Rita T. Lawlor, Claudio Luchini, Laura Sánchez, Juan Manuel Sánchez‐Hidalgo, Sebastián Ventura, Laura Martín-Hijano, Manuel D. Gahete, Aldo Scarpa, Álvaro Arjona‐Sánchez, Alejandro Ibáñez‐Costa, Bruno Sáinz, Raúl M. Luque, Justo P. Castaño
Abstract
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, requiring novel treatments to target both cancer cells and cancer stem cells (CSCs). Altered splicing is emerging as both a novel cancer hallmark and an attractive therapeutic target. The core splicing factor SF3B1 is heavily altered in cancer and can be inhibited by Pladienolide-B, but its actionability in PDAC is unknown. We explored the presence and role of SF3B1 in PDAC and interrogated its potential as an actionable target. METHODS: SF3B1 was analyzed in PDAC tissues, an RNA-seq dataset, and publicly available databases, examining associations with splicing alterations and key features/genes. Functional assays in PDAC cell lines and PDX-derived CSCs served to test Pladienolide-B treatment effects in vitro, and in vivo in zebrafish and mice. RESULTS: SF3B1 was overexpressed in human PDAC and associated with tumor grade and lymph-node involvement. SF3B1 levels closely associated with distinct splicing event profiles and expression of key PDAC players (KRAS, TP53). In PDAC cells, Pladienolide-B increased apoptosis and decreased multiple tumor-related features, including cell proliferation, migration, and colony/sphere formation, altering AKT and JNK signaling, and favoring proapoptotic splicing variants (BCL-XS/BCL-XL, KRASa/KRAS, Δ133TP53/TP53). Importantly, Pladienolide-B similarly impaired CSCs, reducing their stemness capacity and increasing their sensitivity to chemotherapy. Pladienolide-B also reduced PDAC/CSCs xenograft tumor growth in vivo in zebrafish and in mice. CONCLUSION: SF3B1 overexpression represents a therapeutic vulnerability in PDAC, as altered splicing can be targeted with Pladienolide-B both in cancer cells and CSCs, paving the way for novel therapies for this lethal cancer.