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Alterations and molecular targeting of the GSK-3 regulator, PI3K, in head and neck cancer - PubMed

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Alterations and molecular targeting of the GSK-3 regulator, PI3K, in head and neck cancer

Michelle J Lee et al. Biochim Biophys Acta Mol Cell Res. 2020 Jun.

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a highly morbid, genetically unstable disease derived from the mucoepithelium of the upper aerodigestive tract. Recent characterization of this disease has implicated the PI3K-Akt-mTOR pathway as one of the most frequently dysregulated pathways. As such, there are several classes of PI3K inhibitors currently undergoing clinical trials. In this article, we review the PI3K pathway, mutations of this pathway in HNSCC, drugs that target PI3K, the impact of these agents on the PI3K and GSK-3 signaling axes, ongoing clinical trials evaluating PI3K inhibitors, and the challenges of using these drugs in the clinic. This article is part of a Special Issue entitled: GSK-3 and related kinases in cancer, neurological and other disorders edited by James McCubrey, Agnieszka Gizak and Dariusz Rakus.

Keywords: GSK-3; HNSCC; Head and neck squamous cell carcinoma; PI3K; PIK3CA.

Copyright © 2020 Elsevier B.V. All rights reserved.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JRG and DEJ are co-inventors of cyclic STAT3 decoy and have financial interests in STAT3 Therapeutics, Inc. STAT3 Therapeutics, Inc. holds an interest in a cyclic STAT3 decoy oligonucleotide. The remaining authors declare no conflicts.

Figures

Figure 1.
Figure 1.. The PI3K signaling pathway.

PI3K converts PIP2to PIP3, leading to the activation of Akt. Akt inhibits FOXO1, which when active, increases expression of various RTKs including EGFR, IR, and HER3. Akt also activates mTORC1 via inhibition of TSC1/2, leading to stimulation of protein synthesis via activation of S6K and inhibition of 4E-BP1. Inhibition of GSK-3 by Akt results in increased expression of cyclin D and c-Myc and decreased glycogen synthesis.

Figure 2.
Figure 2.. Inhibitory activities and molecular structures of class IA PI3K/mTOR inhibitors.

Different classes of inhibitors target different PI3K isoforms. Alpelisib specifically targets PI3Kα while buparlisib, PX-866, and copanlisib are pan-class IA PI3K inhibitors. SF1126, dactolisib, and gedatolisib are dual class IA PI3K/mTOR inhibitors. Molecular structures were created on PubChem [106].

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