Inhibiting PI3K{beta} with AZD8186 regulates key metabolic pathways in PTEN-null tumours

Purpose: PTEN null tumours become dependent on the PI3Kb isoform and can be targeted by molecules such as the selective PI3Kb inhibitor AZD8186. However beyond the modulation of the canonical PI3K pathway, the consequences of inhibiting PI3Kb are poorly defined. Experimental Design: To determine the broader impact of AZD8186 in PTEN null tumours we performed a genome wide RNAseq analysis of PTEN null triple negative breast tumour xenografts treated with AZD8186. Mechanistic consequences of AZD8186 treatment were examined across a number of PTEN null cell lines and tumour models. Results: AZD8186 treatment resulted in modification of transcript and protein biomarkers associated with cell metabolism. We observed down regulation of cholesterol biosynthesis genes and upregulation of markers associated with metabolic stress. Down regulation of cholesterol biosynthesis proteins such as HMGCS1 occurred in PTEN null cell lines and tumour xenografts sensitive to AZD8186. Therapeutic inhibition of PI3Kb also up-regulated 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 PI3Kb inhibition in PTEN null tumours supporting the concept that targeting PI3Kb 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.

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