Metabolic imaging detects resistance to PI3KΑ inhibition mediated by persistent FOXM1 expression in ER+ breast cancer Journal Article
| Authors: | Ros, S.; Wright, A. J.; D'Santos, P.; Hu, D. E.; Hesketh, R. L.; Lubling, Y.; Georgopoulou, D.; Lerda, G.; Couturier, D. L.; Razavi, P.; Pelossof, R.; Batra, A. S.; Mannion, E.; Lewis, D. Y.; Martin, A.; Baird, R. D.; Oliveira, M.; de Boo, L. W.; Linn, S. C.; Scaltriti, M.; Rueda, O. M.; Bruna, A.; Caldas, C.; Brindle, K. M. |
| Article Title: | Metabolic imaging detects resistance to PI3KΑ inhibition mediated by persistent FOXM1 expression in ER+ breast cancer |
| Abstract: | Ros et al. find that imaging of hyperpolarized [1-13C]pyruvate metabolism allows early detection of response and resistance to PI3Kα inhibition in PIK3CA-mutant ER+ breast cancer, which could be used clinically to guide treatment. Increased expression of FOXM1 results in resistance to PI3Kα inhibition and sustains LDH expression. © 2020 The Authors 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. © 2020 The Authors |
| Keywords: | treatment response; breast cancer; biomarker; fdg-pet; lactate dehydrogenase; mri; hexokinase 2; foxm1; hyperpolarized [1-13c]pyruvate; pi3k alpha inhibition |
| Journal Title: | Cancer Cell |
| Volume: | 38 |
| Issue: | 4 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2020-10-12 |
| Start Page: | 516 |
| End Page: | 533.e9 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2020.08.016 |
| PUBMED: | 32976773 |
| PROVIDER: | scopus |
| PMCID: | PMC7562820 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 November 2020 -- Source: Scopus |
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