ABCG2 Transporter Expression Impacts Group 3 Medulloblastoma Response to Chemotherapy

Cancer Res. 2015 Sep 15;75(18):3879-89. doi: 10.1158/0008-5472.CAN-15-0030. Epub 2015 Jul 21.

Abstract

While a small number of plasma membrane ABC transporters can export chemotherapeutic drugs and confer drug resistance, it is unknown whether these transporters are expressed or functional in less therapeutically tractable cancers such as Group 3 (G3) medulloblastoma. Herein we show that among this class of drug transporters, only ABCG2 was expressed at highly increased levels in human G3 medulloblastoma and a mouse model of this disease. In the mouse model, Abcg2 protein was expressed at the plasma membrane where it functioned as expected on the basis of export of prototypical substrates. By screening ABC substrates against mouse G3 medulloblastoma tumorspheres in vitro, we found that Abcg2 inhibition could potentiate responses to the clinically used drug topotecan, producing a more than 9-fold suppression of cell proliferation. Extended studies in vivo in this model confirmed that Abcg2 inhibition was sufficient to enhance antiproliferative responses to topotecan, producing a significant survival advantage compared with subjects treated with topotecan alone. Our findings offer a preclinical proof of concept for blockade of ABCG2 transporter activity as a strategy to empower chemotherapeutic responses in G3 medulloblastoma.

Publication types

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

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / analysis
  • ATP-Binding Cassette Transporters / antagonists & inhibitors
  • ATP-Binding Cassette Transporters / biosynthesis
  • ATP-Binding Cassette Transporters / physiology*
  • Adenine / analogs & derivatives
  • Adenine / metabolism
  • Animals
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Biological Transport, Active
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Cell Membrane / chemistry
  • Cerebellar Neoplasms / drug therapy*
  • Cerebellar Neoplasms / metabolism
  • Cerebellar Neoplasms / pathology
  • Drug Resistance, Neoplasm / physiology*
  • High-Throughput Screening Assays
  • Humans
  • Medulloblastoma / classification
  • Medulloblastoma / drug therapy*
  • Medulloblastoma / metabolism
  • Medulloblastoma / pathology
  • Mice
  • Mice, Knockout
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / physiology*
  • Propionates / pharmacology
  • Protoporphyrins / biosynthesis
  • Quinolines / pharmacology
  • Topoisomerase I Inhibitors / metabolism
  • Topoisomerase I Inhibitors / pharmacology
  • Topotecan / metabolism
  • Topotecan / pharmacology

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Abcg2 protein, mouse
  • Antineoplastic Agents
  • Neoplasm Proteins
  • Propionates
  • Protoporphyrins
  • Quinolines
  • Topoisomerase I Inhibitors
  • bis(pivaloyloxymethyl)-9-(2-phosphonylmethoxyethyl)adenine
  • verlukast
  • Topotecan
  • protoporphyrin IX
  • Adenine