Metabolic biomarkers for response to PI3K inhibition in basal-like breast cancer

• Published in: Breast cancer research : BCR Vol. 15; no. 1; p. R16
• Main Authors: Moestue, Siver A, Dam, Cornelia G, Gorad, Saurabh S, Kristian, Alexandr, Bofin, Anna, Mælandsmo, Gunhild M, Engebråten, Olav, Gribbestad, Ingrid S, Bjørkøy, Geir
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 28-02-2013; BioMed Central
• Subjects: Analysis; Animals; Basale medisinske, odontologiske og veterinærmedisinske fag: 710; Basic medical, dental and veterinary science disciplines: 710; Biological markers; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Development and progression; Epigenetic inheritance; Female; Genetic aspects; Heterocyclic Compounds, 3-Ring - administration & dosage; Humans; Imidazoles - administration & dosage; Lactates; Medical biochemistry: 726; Medical disciplines: 700; Medisinsk biokjemi: 726; Medisinske Fag: 700; Neoplasms, Basal Cell - drug therapy; Neoplasms, Basal Cell - genetics; Neoplasms, Basal Cell - pathology; Nuclear magnetic resonance spectroscopy; Phenotype; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Prognosis; Proto-Oncogene Proteins c-akt - genetics; Quinolines - administration & dosage; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - genetics; VDP; Xenograft Model Antitumor Assays; Denmark
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/bcr3391

The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in cancer cells through numerous mutations and epigenetic changes. The recent development of inhibitors targeting different components of the PI3K pathway may represent a valuable treatment alternative. However, predicting efficacy of these drugs is challenging, and methods for therapy monitoring are needed. Basal-like breast cancer (BLBC) is an aggressive breast cancer subtype, frequently associated with PI3K pathway activation. The objectives of this study were to quantify the PI3K pathway activity in tissue sections from xenografts representing basal-like and luminal-like breast cancer before and immediately after treatment with PI3K inhibitors, and to identify metabolic biomarkers for treatment response.
Tumor-bearing animals (n = 8 per treatment group) received MK-2206 (120 mg/kg/day) or BEZ235 (50 mg/kg/day) for 3 days. Activity in the PI3K/Akt/mammalian target of rapamycin pathway in xenografts and human biopsies was evaluated using a novel method for semiquantitative assessment of Aktser473 phosphorylation. Metabolic changes were assessed by ex vivo high-resolution magic angle spinning magnetic resonance spectroscopy.
Using a novel dual near-infrared immunofluorescent imaging method, basal-like xenografts had a 4.5-fold higher baseline level of pAktser473 than luminal-like xenografts. Following treatment, basal-like xenografts demonstrated reduced levels of pAktser473 and decreased proliferation. This correlated with metabolic changes, as both MK-2206 and BEZ235 reduced lactate concentration and increased phosphocholine concentration in the basal-like tumors. BEZ235 also caused increased glucose and glycerophosphocholine concentrations. No response to treatment or change in metabolic profile was seen in luminal-like xenografts. Analyzing tumor sections from five patients with BLBC demonstrated that two of these patients had an elevated pAktser473 level.
The activity of the PI3K pathway can be determined in tissue sections by quantitative imaging using an antibody towards pAktser473. Long-term treatment with MK-2206 or BEZ235 resulted in significant growth inhibition in basal-like, but not luminal-like, xenografts. This indicates that PI3K inhibitors may have selective efficacy in basal-like breast cancer with increased PI3K signaling, and identifies lactate, phosphocholine and glycerophosphocholine as potential metabolic biomarkers for early therapy monitoring. In human biopsies, variable pAktser473 levels were observed, suggesting heterogeneous PI3K signaling activity in BLBC.