التفاصيل البيبلوغرافية
| العنوان: |
Metabolic Imaging Detects Resistance to PI3Kα Inhibition Mediated by Persistent FOXM1 Expression in ER+ Breast Cancer. |
| المؤلفون: |
Ros, Susana1,2 (AUTHOR) susana.ros@cruk.cam.ac.uk, Wright, Alan J.1,2 (AUTHOR), D'Santos, Paula1,2 (AUTHOR), Hu, De-en1,2 (AUTHOR), Hesketh, Richard L.1,2 (AUTHOR), Lubling, Yaniv1,2 (AUTHOR), Georgopoulou, Dimitra1,2 (AUTHOR), Lerda, Giulia1,2 (AUTHOR), Couturier, Dominique-Laurent1 (AUTHOR), Razavi, Pedram3 (AUTHOR), Pelossof, Rapahel3 (AUTHOR), Batra, Ankita S.1,2 (AUTHOR), Mannion, Elizabeth1,2 (AUTHOR), Lewis, David Y.1,2 (AUTHOR), Martin, Alistair1,2 (AUTHOR), Baird, Richard D.4 (AUTHOR), Oliveira, Mafalda5 (AUTHOR), de Boo, Leonora W.6 (AUTHOR), Linn, Sabine C.6,7 (AUTHOR), Scaltriti, Maurizio3 (AUTHOR) |
| المصدر: |
Cancer Cell. Oct2020, Vol. 38 Issue 4, p516-516. 1p. |
| مصطلحات موضوعية: |
*BREAST cancer, *POSITRON emission tomography, *ESTROGEN receptors, *LACTATE dehydrogenase, *PYRUVATES, *PHOSPHATIDYLINOSITOL 3-kinases, *LACTATES |
| مصطلحات جغرافية: |
HONG Kong (China) |
| مستخلص: |
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. • Imaging hyperpolarized [1-13C]pyruvate metabolism detects response to PI3Kα inhibitors • PI3Kα inhibitors downregulate FOXM1 expression in ER+ breast tumor models • FOXM1 induces LDH expression and 13C label exchange between pyruvate and lactate • Imaging [1-13C]pyruvate metabolism could be used clinically to guide treatment 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. [ABSTRACT FROM AUTHOR] |
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