GSK3βhigh/NFATc1high subtype targeting overcomes therapy resistance in pancreatic cancer through transcriptional induction of homologous recombination repair.

BACKGROUND

The efficacy of pharmacological glycogen synthase kinase-3β (GSK3β) inhibition is currently being investigated in unselected cohorts of metastatic pancreatic ductal adenocarcinoma (PDAC). Here, we sought to determine the clinical significance of nuclear GSK3β accumulation in patients with resectable PDAC.

OBJECTIVE

This study aimed to explore the therapeutic potential and underlying mechanisms of GSK3β pathway disruption in PDAC with enriched nuclear GSK3β levels.

DESIGN

We investigated the activation and function of GSK3β and its downstream transcription factor NFATc1 in tumour recurrence, growth and resistance using human PDAC tissues, patient-derived organoids and tumour cells, PDAC explants, cell lines and murine models. GSK3β signalling was disrupted using genetic and pharmacological approaches. Live-cell imaging, proliferation, homologous recombination (HR) repair and comet assays, messenger RNA sequencing and chromatin immunoprecipitation were used to explore GSK3β-NFATc1 signalling-mediated target gene regulation in DNA repair, growth and resistance.

RESULTS

Nuclear GSK3β accumulates in a subset of resected PDAC and promotes proliferation and DNA repair through NFATc1. The GSK3βhigh/NFATc1high subtype accounts for 14% of resected PDAC and is associated with rapid tumour recurrence and poor survival. The GSK3β-NFATc1 signalling pathway contributes to cisplatin resistance by inducing BRCA genes transcription, which facilitates HR-mediated DNA double-strand breaks (DSBs) repair. Disruption of the GSK3β-NFATc1 axis impairs HR-driven DSB repair, increasing cisplatin sensitivity in vitro and in preclinical PDAC models.

CONCLUSION

We have identified a highly aggressive GSK3βhigh/NFATc1high subtype that predicts early recurrence, poor survival and cisplatin resistance in PDAC. This subtype reveals new treatment vulnerabilities suggesting that patients with PDAC may benefit from stratification-based tailored treatment strategies.