Nuclear GSK3β/NFATc1 axis controls DNA repair mechanisms and drives therapy resistance in PDAC

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. The pronounced heterogeneity of the PDAC tumors limits the efficacy of current treatment regimens underscoring the identification of new molecular subtypes and stratified therapeutic strategies. The efficacy and tolerability of pharmacological GSK3β inhibition is currently being investigated in unselected cohorts of metastatic PDAC.

Objectives: Here, we investigate the clinical relevance of concurrent nuclear accumulation of GSK3β and NFATc1 in resectable PDAC and explore the therapeutic potential and underlying mechanisms of GSK3β/NFATc1 pathway disruption.

Methodology: To explore the therapeutic potential of nuclear GSK3β/NFATc1 cooperation in tumor growth and therapy resistance, we employed a range of in vivo and in vitro experimental models including human PDAC tissues, ex-vivo tumor slices, organoids, PDX-derived primary tumor cells and murine PDAC subjected to GSK3β/NFATc1 signaling disruption using genetic and pharmacological approaches. Live-cell imaging, colony formation, FACS and proliferation assays were carried out to investigate the tumor growth and resistance, Additionally, mRNA sequencing, chromatin immunoprecipitation and homologous recombination repair (HRR) studies were performed to explore target genes regulation in DNA repair, growth and resistance.

Results: Nuclear GSK3β and NFATc1 concurrently accumulate in a subset of resected PDAC patients, named as GSK3β^high/NFATc1^high subtype and accounts for approximately 14% of resected PDAC. This subtype is associated with rapid recurrence and poor survival. GSK3β-NFATc1 signaling promotes cisplatin resistance through transcriptional induction of BRCA and FANC genes and increased HRR-mediated DNA repair. Pharmacological and/or genetic disruption of the GSK3β-NFATc1 axis impairs HRR machinery and causes an “inducible BRCAness” phenotype and increases PDAC sensitivity to cisplatin treatment in in vitro as well as in vivo.

Conclusions: We define a distinct and clinically relevant highly aggressive GSK3β^high/NFATc1^high subtype that predicts poor prognosis and cisplatin resistance in resectable PDAC. This subtype also uncovers novel vulnerabilities offering new strategies for personalized treatment.

Publication History

Article published online:
04 September 2025