Preclinical Evaluation of Dual PI3K-mTOR Inhibitors and Histone Deacetylase Inhibitors in Head and Neck Squamous Cell Carcinoma

Overview

Journal Br J Cancer

Specialty Oncology

Date 2011 Nov 26

PMID 22116303

Citations 29

Authors

R B Erlich

Z Kherrouche

D Rickwood

L Endo-Munoz

S Cameron

A Dahler

M Hazar-Rethinam

L M de Long

K Wooley

A Guminski

N A Saunders

Affiliations

Soon will be listed here.

Abstract

Background: We examine the potential value of a series of clinically relevant PI3K-mTOR inhibitors alone, or in combination with histone deacetylase inhibitors, in a model of head and neck squamous cell carcinoma (HNSCC).

Methods: Head and neck squamous cell carcinoma cell lines, human keratinocyte and HNSCC xenograft models were treated with histone deacetylase inhibitors (HDACIs) and new generation PI3K and dual PI3K-mTOR inhibitors either alone or in combination. Cell and tumour tissue viability and proliferation were then determined in vitro and in vivo.

Results: Phosphatidylinositol-3-phosphate kinase, AKT and dual PI3K-mTOR inhibitors caused marked in vitro enhancement of cytotoxicity induced by HDACIs in HNSCC cancer cells. This effect correlates with AKT inhibition and is attenuated by expression of constitutively active AKT. Histone deacetylase inhibitor and phosphatidylinositol-3-phosphate kinase inhibitors (PI3KIs) inhibited tumour growth in xenograft models of HNSCC. Importantly, we observed intratumoural HDAC inhibition and PI3K inhibition as assessed by histone H3 acetylation status and phospho-AKT staining, respectively. However, we saw no evidence of improved efficacy with an HDACI/PI3KI combination.

Interpretation: That PI3K and dual PI3K-mTOR inhibitors possess antitumour effect against HNSCC in vivo.

Citing Articles

The Role of the PI3K/Akt/mTOR Axis in Head and Neck Squamous Cell Carcinoma.

Jiang Q, Xiao J, Hsieh Y, Kumar N, Han L, Zou Y Biomedicines. 2024; 12(7).

PMID: 39062182 PMC: 11274428. DOI: 10.3390/biomedicines12071610.

Targeted therapy for head and neck cancer: signaling pathways and clinical studies.

Li Q, Tie Y, Alu A, Ma X, Shi H Signal Transduct Target Ther. 2023; 8(1):31.

PMID: 36646686 PMC: 9842704. DOI: 10.1038/s41392-022-01297-0.

Histone Deacetylase Inhibitors as Multitarget-Directed Epi-Drugs in Blocking PI3K Oncogenic Signaling: A Polypharmacology Approach.

Ranganna K, Selvam C, Shivachar A, Yousefipour Z Int J Mol Sci. 2020; 21(21).

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Identification of Targetable Pathways in Oral Cancer Patients via Random Forest and Chemical Informatics.

Schomberg J Cancer Inform. 2019; 18:1176935119889911.

PMID: 31819345 PMC: 6883365. DOI: 10.1177/1176935119889911.

A PI3K/AKT Scaffolding Protein, IQ Motif-Containing GTPase Associating Protein 1 (IQGAP1), Promotes Head and Neck Carcinogenesis.

Wei T, Choi S, Buehler D, Anderson R, Lambert P Clin Cancer Res. 2019; 26(1):301-311.

PMID: 31597661 PMC: 6942630. DOI: 10.1158/1078-0432.CCR-19-1063.

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