Inhibiting PI3Kβ with AZD8186 Regulates Key Metabolic Pathways in PTEN-Null Tumors.

Autor:	Lynch JT; Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom., Polanska UM; Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom., Delpuech O; Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom., Hancox U; Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Alderley Park, United Kingdom., Trinidad AG; Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom., Michopoulos F; Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Alderley Park, United Kingdom., Lenaghan C; Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Alderley Park, United Kingdom., McEwen R; Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom., Bradford J; Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Alderley Park, United Kingdom., Polanski R; Department of Oncology and Metabolism, University of Sheffield, Sheffield, South Yorkshire, United Kingdom., Ellston R; Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Alderley Park, United Kingdom., Avivar-Valderas A; Discovery Sciences, AstraZeneca, Cambridge, United Kingdom., Pilling J; Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Alderley Park, United Kingdom., Staniszewska A; Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom., Cumberbatch M; Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom., Critchlow SE; Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom., Cruzalegui F; Discovery Sciences, AstraZeneca, Cambridge, United Kingdom., Barry ST; Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom. Simon.T.Barry@astrazeneca.com.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2017 Dec 15; Vol. 23 (24), pp. 7584-7595. Date of Electronic Publication: 2017 Oct 02.
DOI:	10.1158/1078-0432.CCR-17-0676
Abstrakt:	Purpose: PTEN-null tumors become dependent on the PI3Kβ isoform and can be targeted by molecules such as the selective PI3Kβ inhibitor AZD8186. However, beyond the modulation of the canonical PI3K pathway, the consequences of inhibiting PI3Kβ are poorly defined. Experimental Design: To determine the broader impact of AZD8186 in PTEN-null tumors, we performed a genome-wide RNA-seq analysis of PTEN-null triple-negative breast tumor xenografts treated with AZD8186. Mechanistic consequences of AZD8186 treatment were examined across a number of PTEN-null cell lines and tumor models. Results: AZD8186 treatment resulted in modification of transcript and protein biomarkers associated with cell metabolism. We observed downregulation of cholesterol biosynthesis genes and upregulation of markers associated with metabolic stress. Downregulation of cholesterol biosynthesis proteins, such as HMGCS1, occurred in PTEN-null cell lines and tumor xenografts sensitive to AZD8186. Therapeutic inhibition of PI3Kβ also upregulated PDHK4 and increased PDH phosphorylation, indicative of reduced carbon flux into the TCA cycle. Consistent with this, metabolomic analysis revealed a number of changes in key carbon pathways, nucleotide, and amino acid biosynthesis. Conclusions: This study identifies novel mechanistic biomarkers of PI3Kβ inhibition in PTEN-null tumors supporting the concept that targeting PI3Kβ may exploit a metabolic dependency that contributes to therapeutic benefit in inducing cell stress. Considering these additional pathways will guide biomarker and combination strategies for this class of agents. Clin Cancer Res; 23(24); 7584-95. ©2017 AACR . (©2017 American Association for Cancer Research.)
Databáze:	MEDLINE
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