Glycogen synthase kinase-3 beta inhibitors as novel cancer treatments and modulators of antitumor immune responses

Abstract

As a kinase at the crossroads of numerous metabolic and cell growth signaling pathways, glycogen synthase kinase-3 beta (GSK-3β) is a highly desirable therapeutic target in cancer. Despite its involvement in pathways associated with the pathogenesis of several malignancies, no selective GSK-3β inhibitor has been approved for the treatment of cancer. The regulatory role of GSK-3β in apoptosis, cell cycle, DNA repair, tumor growth, invasion, and metastasis reflects the therapeutic relevance of this target and provides the rationale for drug combinations. Emerging data on GSK-3β as a mediator of anticancer immune response also highlight the potential clinical applications of novel selective GSK-3β inhibitors that are entering clinical studies. This manuscript reviews the preclinical and early clinical results with GSK-3β inhibitors and delineates the developmental therapeutics landscape for this potentially important target in cancer therapy.

Keywords: GSK-3β; cancer; clinical trial; immunotherapy.

Figures

Figure 1.

GSK-3β-mediated signaling pathways. When the Wnt ligand is present, it inhibits GSK-3β on the target cell, which suppresses β-catenin phosphorylation and makes it stable in cytoplasm. Stable β-catenin translocates into the nucleus promoting transcription of target genes such as c-Myc and cyclin-D. GSK-3β prevents epithelial–mesenchymal transition (EMT) by inhibiting Snail, a repressor of E-cadherin gene. GSK-3β phosphorylates several upstream and downstream components of the PI3K/AKT/mTOR pathway, and AKT can phosphorylate GSK-3β and inhibit its activity.

Figure 2.

Genomic alterations in GSK-3β. The landscape of GSK-3β genomic alterations among cancer types from the cBio Cancer Genomics Portal dataset.

Figure 3.

Proposed model for regulation of PD-1 by GSK-3β signaling. In the presence of anti-PD-1, activation of Src homology region domain-containing phosphatase (SHP) is inhibited, thus allowing for the phosphorylation of the CD28 phosphoinositide 3-kinase (PI3K)-binding site which leads GSK-3β inhibition via AKT activation. GSK-3β induces the transcription of the transcription factor Tbx21 (Tbet) which in turn inhibits transcription and expression of PD-L1.