Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases

Nat Med. 2016 Jul;22(7):723-6. doi: 10.1038/nm.4120. Epub 2016 Jun 6.

Abstract

Brain metastases represent the greatest clinical challenge in treating HER2-positive breast cancer. We report the development of orthotopic patient-derived xenografts (PDXs) of HER2-expressing breast cancer brain metastases (BCBM), and their use for the identification of targeted combination therapies. Combined inhibition of PI3K and mTOR resulted in durable tumor regressions in three of five PDXs, and therapeutic response was correlated with a reduction in the phosphorylation of 4EBP1, an mTORC1 effector. The two nonresponding PDXs showed hypermutated genomes with enrichment of mutations in DNA-repair genes, which suggests an association of genomic instability with therapeutic resistance. These findings suggest that a biomarker-driven clinical trial of PI3K inhibitor in combination with an mTOR inhibitor should be conducted for patients with HER2-positive BCBM.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Aminopyridines / pharmacology*
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / secondary
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carrier Proteins / drug effects
  • Carrier Proteins / metabolism
  • Caspase 3 / drug effects
  • Caspase 3 / metabolism
  • Cell Cycle Proteins
  • DNA Repair / genetics
  • Drug Resistance, Neoplasm / genetics
  • Drug Therapy, Combination
  • Eukaryotic Initiation Factors
  • Everolimus / pharmacology*
  • Female
  • Gene Expression Profiling
  • Genomic Instability
  • Humans
  • Immunohistochemistry
  • Ki-67 Antigen / drug effects
  • Ki-67 Antigen / metabolism
  • Magnetic Resonance Imaging
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, SCID
  • Molecular Targeted Therapy
  • Morpholines / pharmacology*
  • Multiprotein Complexes / antagonists & inhibitors*
  • Neoplasm Transplantation
  • Phosphoinositide-3 Kinase Inhibitors*
  • Phosphoproteins / drug effects
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Receptor, ErbB-2 / metabolism
  • Remission Induction
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • Xenograft Model Antitumor Assays

Substances

  • Adaptor Proteins, Signal Transducing
  • Aminopyridines
  • Antineoplastic Agents
  • Carrier Proteins
  • Cell Cycle Proteins
  • Eif4ebp1 protein, mouse
  • Eukaryotic Initiation Factors
  • Ki-67 Antigen
  • Morpholines
  • Multiprotein Complexes
  • NVP-BKM120
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoproteins
  • Everolimus
  • TOR Serine-Threonine Kinases
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Mechanistic Target of Rapamycin Complex 1
  • Casp3 protein, mouse
  • Caspase 3