Metabolic Response to Everolimus in Patient-derived Xenografts of Triple Negative Breast Cancer
Magnetic resonance based metabolic profiles of breast tumor tissue (n=103 samples) from triple negative breast cancer (TNBC) patient-derived xenografts (PDX) were used to evaluate treatment with the mTOR inhibitor Everolimus. Levels of 17 metabolites were calculated by integration and were used, along with lactate/glucose, taurine/creatine, and glycerophosphocholine/phosphocholine ratios, to build a multivariate PLS-DA model discriminating treated from control PDX, achieving an accuracy of 67% (p=0.003). Univariate linear mixed models revealed a significant increase (q ≤ 0.05) in glucose, glutamine, alanine, and glycerophosphocholine/phosphocholine, and decrease in phosphocholine, and lactate/glucose in treated PDX compared to controls, in accordance with PLS-DA loadings. This suggests reduced glycolytic lactate production and glutaminolysis after treatment, consistent with PI3K/AKT/mTOR signaling pathway inhibition1. However, no differences could be detected between responders and non-responders. PLS-DA was additionally employed on spectral profiles to investigate metabolic differences between controls (n=53) expressing or not expressing the tumor suppressors INPP4B and PTEN (determined by immunohistochemistry), which negatively regulate mTOR. Expression of INPP4B was successfully discriminated with an accuracy of 69% (p=0.009), while PTEN expression discrimination approached significance (64% accuracy, p=0.055). INPP4B expression was associated with increased phosphocholine, glycine, creatine, alanine, and lactate, and decreased glycerophosphocholine and taurine, according to PLS-DA loadings.
