Metabolic Response to Everolimus in Patient-Derived Triple-Negative Breast Cancer Xenografts
Leslie R Euceda1, Deborah K Hill1,2, Endre Stokke1
1Department of Circulation and Medical Imaging, NTNU, The Norwegian University of Science and Technology , Trondheim 7489, Norway.
Abstract:
Patients with triple-negative breast cancer (TNBC) are unresponsive to endocrine and anti-HER2 pharmacotherapy, limiting their therapeutic options to chemotherapy. TNBC is frequently associated with abnormalities in the PI3K/AKT/mTOR signaling pathway; drugs targeting this pathway are currently being evaluated in these patients. However, the response is variable, partly due to heterogeneity within TNBC, conferring a need to identify biomarkers predicting response and resistance to targeted therapy. In this study, we used a metabolomics approach to assess response to the mTOR inhibitor everolimus in a panel of TNBC patient-derived xenografts (PDX) (n = 103 animals). Tumor metabolic profiles were acquired using high-resolution magic angle spinning magnetic resonance spectroscopy. Partial least-squares-discriminant analysis on relative metabolite concentrations discriminated treated xenografts from untreated controls with an accuracy of 67% (p = 0.003). Multilevel linear mixed-effects models (LMM) indicated reduced glycolytic lactate production and glutaminolysis after treatment, consistent with PI3K/AKT/mTOR pathway inhibition. Although inherent metabolic heterogeneity between different PDX models seemed to hinder prediction of treatment response, the metabolic effects following treatment were more pronounced in responding xenografts compared to nonresponders. Additionally, the metabolic information predicted p53 mutation status, which may provide complementary insight into the interplay between PI3K signaling and other drivers of disease progression.
Insights
Metabolomics identified metabolic shifts in triple-negative breast cancer (TNBC) xenografts treated with an mTOR inhibitor. These metabolic changes, though affected by tumor heterogeneity, showed potential for predicting treatment response and p53 mutation status in TNBC.
Area of Science:
- Oncology
- Biochemistry
- Metabolomics
Background:
- Triple-negative breast cancer (TNBC) lacks targeted therapies beyond chemotherapy.
- The PI3K/AKT/mTOR pathway is frequently dysregulated in TNBC, making it a target for novel therapeutics.
- Predicting response and resistance to targeted therapies in heterogeneous TNBC remains a challenge.
Purpose of the Study:
- To investigate the utility of metabolomics in assessing response to the mTOR inhibitor everolimus in TNBC patient-derived xenografts (PDX).
- To identify metabolic biomarkers that predict response and resistance to PI3K/AKT/mTOR pathway inhibition in TNBC.
- To explore the relationship between tumor metabolism, treatment response, and p53 mutation status.
Main Methods:
- Utilized a metabolomics approach on 103 TNBC PDX models treated with everolimus.
- Acquired tumor metabolic profiles using high-resolution magic angle spinning magnetic resonance spectroscopy.
- Analyzed data using partial least-squares-discriminant analysis and multilevel linear mixed-effects models.
Main Results:
- Metabolomics successfully discriminated treated from untreated xenografts (67% accuracy, p=0.003).
- Everolimus treatment led to reduced lactate production and glutaminolysis, confirming pathway inhibition.
- Metabolic effects were more pronounced in responding xenografts, and metabolic data predicted p53 mutation status.
Conclusions:
- Metabolomics can reveal treatment effects and identify potential biomarkers for targeted therapy response in TNBC.
- Tumor metabolic heterogeneity presents a challenge but does not preclude the identification of treatment-related metabolic signatures.
- Metabolic profiling may offer complementary insights into TNBC biology and treatment response, potentially including p53 status.
