Metabolic Imaging Detects Resistance to PI3Kα Inhibition Mediated by Persistent FOXM1 Expression in ER+ Breast Cancer

Cancer Cell. 2020 Oct 12;38(4):516-533.e9. doi: 10.1016/j.ccell.2020.08.016. Epub 2020 Sep 24.

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.

Keywords: FDG-PET; FOXM1; MRI; PI3K alpha inhibition; biomarker; breast cancer; hexokinase 2; hyperpolarized [1-(13)C]pyruvate; lactate dehydrogenase; treatment response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Class I Phosphatidylinositol 3-Kinases / metabolism
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Forkhead Box Protein M1 / genetics
  • Forkhead Box Protein M1 / metabolism*
  • Fulvestrant / administration & dosage
  • Humans
  • Imidazoles / administration & dosage
  • MCF-7 Cells
  • Magnetic Resonance Imaging / methods
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Oxazepines / administration & dosage
  • Protein Kinase Inhibitors / pharmacology*
  • Receptors, Estrogen / metabolism
  • Tamoxifen / administration & dosage
  • Xenograft Model Antitumor Assays / methods

Substances

  • 2-(3-(2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo(f)imidazo(1,2-d)(1,4)oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide
  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • Imidazoles
  • Oxazepines
  • Protein Kinase Inhibitors
  • Receptors, Estrogen
  • Tamoxifen
  • Fulvestrant
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human