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

James T Lynch1, Urszula M Polanska1, Oona Delpuech1

  • 1Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|October 4, 2017
PubMed

Insights

Targeting PI3Kβ with AZD8186 in PTEN-null tumors impacts cell metabolism, downregulating cholesterol synthesis and increasing metabolic stress markers, revealing new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • PTEN-null tumors exhibit dependency on PI3Kβ.
  • Selective PI3Kβ inhibitors like AZD8186 offer a therapeutic approach.
  • The broader consequences of PI3Kβ inhibition are not fully understood.

Purpose of the Study:

  • To investigate the comprehensive effects of AZD8186 in PTEN-null tumors.
  • To identify mechanistic consequences beyond canonical PI3K pathway modulation.
  • To explore potential metabolic vulnerabilities exploited by PI3Kβ inhibition.

Main Methods:

  • Genome-wide RNA-seq analysis of PTEN-null triple-negative breast tumor xenografts treated with AZD8186.
  • Examination of mechanistic consequences in PTEN-null cell lines and tumor models.
  • Metabolomic analysis of key carbon pathways, nucleotide, and amino acid biosynthesis.

Main Results:

  • AZD8186 treatment altered transcript and protein biomarkers related to cell metabolism.
  • Observed downregulation of cholesterol biosynthesis genes (e.g., HMGCS1) and upregulation of metabolic stress markers.
  • PI3Kβ inhibition led to increased PDHK4, PDH phosphorylation, and altered carbon flux into the TCA cycle.

Conclusions:

  • Identified novel mechanistic biomarkers of PI3Kβ inhibition in PTEN-null tumors.
  • Suggests targeting PI3Kβ exploits metabolic dependencies, inducing cell stress for therapeutic benefit.
  • Highlights the importance of considering additional pathways for biomarker and combination strategies.

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