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Metabolic Imaging Detects Resistance to PI3Kα Inhibition Mediated by Persistent FOXM1 Expression in ER+ Breast Cancer.
Ros, Susana; Wright, Alan J; D'Santos, Paula; Hu, De-En; Hesketh, Richard L; Lubling, Yaniv; Georgopoulou, Dimitra; Lerda, Giulia; Couturier, Dominique-Laurent; Razavi, Pedram; Pelossof, Rapahel; Batra, Ankita S; Mannion, Elizabeth; Lewis, David Y; Martin, Alistair; Baird, Richard D; Oliveira, Mafalda; de Boo, Leonora W; Linn, Sabine C; Scaltriti, Maurizio; Rueda, Oscar M; Bruna, Alejandra; Caldas, Carlos; Brindle, Kevin M.
Affiliation
  • Ros S; Cancer 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. Electronic address: susana.ros@cruk.cam.ac.uk.
  • Wright AJ; Cancer 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.
  • D'Santos P; Cancer 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.
  • Hu DE; Cancer 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.
  • Hesketh RL; Cancer 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.
  • Lubling Y; Cancer 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.
  • Georgopoulou D; Cancer 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.
  • Lerda G; Cancer 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.
  • Couturier DL; Cancer Research UK Cambridge Institute and Department of Oncology, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.
  • Razavi P; Human Oncology and Pathogenesis Program, X and Department of Pathology, Y and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Pelossof R; Human Oncology and Pathogenesis Program, X and Department of Pathology, Y and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Batra AS; Cancer 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.
  • Mannion E; Cancer 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.
  • Lewis DY; Cancer 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.
  • Martin A; Cancer 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.
  • Baird RD; Breast Cancer Research Programme, Cancer Research UK Cambridge Centre, Cambridge, UK.
  • Oliveira M; Medical Oncology, Vall d'Hebron Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
  • de Boo LW; Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • Linn SC; Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
  • Scaltriti M; Human Oncology and Pathogenesis Program, X and Department of Pathology, Y and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Rueda OM; Cancer 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.
  • Bruna A; Cancer 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.
  • Caldas C; Cancer 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.
  • Brindle KM; Cancer 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; Department of Biochemistry, University of Cambridge, Cambridge UK. Electronic address: kmb1001@cam.ac.uk.
Cancer Cell ; 38(4): 516-533.e9, 2020 10 12.
Article in En | MEDLINE | ID: mdl-32976773
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Breast Neoplasms / Antineoplastic Combined Chemotherapy Protocols / Protein Kinase Inhibitors / Class I Phosphatidylinositol 3-Kinases / Forkhead Box Protein M1 Type of study: Prognostic_studies Limits: Animals / Female / Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2020 Type: Article
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Breast Neoplasms / Antineoplastic Combined Chemotherapy Protocols / Protein Kinase Inhibitors / Class I Phosphatidylinositol 3-Kinases / Forkhead Box Protein M1 Type of study: Prognostic_studies Limits: Animals / Female / Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2020 Type: Article