GSK3β as a novel promising target to overcome chemoresistance in pancreatic cancer

Pancreatic cancer is an aggressive malignancy with increasing incidence and poor prognosis due to its late diagnosis and intrinsic chemoresistance. Most pancreatic cancer patients present with locally advanced or metastatic disease characterized by inherent resistance to chemotherapy. These features pose a series of therapeutic challenges and new targets are urgently needed. Glycogen synthase kinase 3 beta (GSK3 beta) is a conserved serine/threonine kinase, which regulates key cellular processes including cell proliferation, DNA repair, cell cycle progression, signaling and metabolic pathways. GSK3 beta is implicated in non-malignant and malignant diseases including inflammation, neurodegenerative diseases, diabetes and cancer. GSK3 beta recently emerged among the key factors involved in the onset and progression of pancreatic cancer, as well as in the acquisition of chemoresistance. Intensive research has been conducted on key oncogenic functions of GSK3 beta and its potential as a druggable target; currently developed GSK3 beta inhibitors display promising results in preclinical models of distinct tumor types, including pancreatic cancer. Here, we review the latest findings about GSK-3 beta biology and its role in the development and progression of pancreatic cancer. Moreover, we discuss therapeutic agents targeting GSK3 beta that could be administered as monotherapy or in combination with other drugs to surmount chemoresistance. Several studies are also defining potential gene signatures to identify patients who might benefit from GSK3 beta-based therapeutic intervention. This detailed overview emphasizes the urgent need of additional molecular studies on the impact of GSK3 beta inhibition as well as structural analysis of novel compounds and omics studies of predictive biomarkers.

Automated summary

Pancreatic cancer is a challenging malignancy characterized by late diagnosis and chemoresistance, highlighting the need for new therapeutic targets. GSK3 beta, a conserved serine/threonine kinase, plays a crucial role in the development and progression of pancreatic cancer, offering potential as a target for overcoming chemoresistance. Studies on GSK3 beta inhibitors in preclinical models show promising results, indicating its significance in cancer treatment.