Metabolic Imaging Detects Resistance to PI3Kα Inhibition Mediated by Persistent FOXM1 Expression in ER+ Breast Cancer
Susana Ros1, Alan J Wright1, Paula D'Santos1
1Cancer Research UK Cambridge Institute and Department of Oncology, Li Ka Shing Centre, University of Cambridge, Cambridge, UK; Cancer Research UK Cambridge Cancer Centre, Cambridge, UK.
Abstract:
PIK3CA, encoding the PI3Kα isoform, is the most frequently mutated oncogene in estrogen receptor (ER)-positive breast cancer. Isoform-selective PI3K inhibitors are used clinically but intrinsic and acquired resistance limits their utility. Improved selection of patients that will benefit from these drugs requires predictive biomarkers. We show here that persistent FOXM1 expression following drug treatment is a biomarker of resistance to PI3Kα inhibition in ER+ breast cancer. FOXM1 drives expression of lactate dehydrogenase (LDH) but not hexokinase 2 (HK-II). The downstream metabolic changes can therefore be detected using MRI of LDH-catalyzed hyperpolarized 13C label exchange between pyruvate and lactate but not by positron emission tomography measurements of HK-II-mediated trapping of the glucose analog 2-deoxy-2-[18F]fluorodeoxyglucose. Rapid assessment of treatment response in breast cancer using this imaging method could help identify patients that benefit from PI3Kα inhibition and design drug combinations to counteract the emergence of resistance.
Insights
Persistent FOXM1 expression indicates resistance to PI3Kα inhibitors in ER-positive breast cancer. This resistance can be detected using MRI, aiding treatment selection and overcoming drug resistance in breast cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Medical Imaging
Background:
- PIK3CA mutations are common in ER-positive breast cancer, driving oncogenesis.
- PI3Kα inhibitors are a clinical treatment, but resistance limits efficacy.
- Predictive biomarkers are needed to identify patients who will respond to PI3Kα inhibitors.
Purpose of the Study:
- To identify biomarkers predicting resistance to PI3Kα inhibitors in ER-positive breast cancer.
- To investigate the role of FOXM1 in mediating resistance to PI3Kα inhibition.
- To explore metabolic imaging techniques for assessing treatment response.
Main Methods:
- Analysis of FOXM1 expression in response to PI3Kα inhibitor treatment.
- Investigating the downstream targets of FOXM1, including lactate dehydrogenase (LDH) and hexokinase 2 (HK-II).
- Utilizing magnetic resonance imaging (MRI) of hyperpolarized 13C-labeled pyruvate-to-lactate exchange to detect metabolic changes.
Main Results:
- Persistent FOXM1 expression after treatment is a biomarker of resistance to PI3Kα inhibition.
- FOXM1 upregulates LDH but not HK-II.
- MRI can detect LDH-driven metabolic changes, distinguishing it from PET imaging of HK-II.
Conclusions:
- FOXM1 is a key mediator of resistance to PI3Kα inhibitors in ER-positive breast cancer.
- MRI of LDH-catalyzed metabolism offers a non-invasive method to assess treatment response and resistance.
- This imaging approach can guide patient selection for PI3Kα inhibitors and inform strategies to overcome resistance.
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