title: ABCG2 Transporter Expression Impacts Group 3 Medulloblastoma Response to Chemotherapy.
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.
authors.affiliation: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Marie
authors.initials: M
authors.lastname: Morfouace
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Satish
authors.initials: S
authors.lastname: Cheepala
authors.affiliation: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Sadhana
authors.initials: S
authors.lastname: Jackson
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Yu
authors.initials: Y
authors.lastname: Fukuda
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Yogesh T
authors.initials: YT
authors.lastname: Patel
authors.affiliation: Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Soghra
authors.initials: S
authors.lastname: Fatima
authors.affiliation: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kawauchi
authors.affiliation: Department of Chemical Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Anang A
authors.initials: AA
authors.lastname: Shelat
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.affiliation: Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Sorrentino
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee. martine.roussel@stjude.org john.schuetz@stjude.org.
authors.forename: John D
authors.initials: JD
authors.lastname: Schuetz
authors.affiliation: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee. martine.roussel@stjude.org john.schuetz@stjude.org.
authors.forename: Martine F
authors.initials: MF
authors.lastname: Roussel
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000032:analysis / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D000225:Adenine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001693:Biological Transport, Active; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D057166:High-Throughput Screening Assays; D006801:Humans; D008527:Medulloblastoma / Q000145:classification / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D011422:Propionates / Q000494:pharmacology; D011524:Protoporphyrins / Q000096:biosynthesis; D011804:Quinolines / Q000494:pharmacology; D059004:Topoisomerase I Inhibitors / Q000378:metabolism / Q000494:pharmacology; D019772:Topotecan / Q000378:metabolism / Q000494:pharmacology
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D011422:Propionates; D011524:Protoporphyrins; D011804:Quinolines; D059004:Topoisomerase I Inhibitors; C089823:bis(pivaloyloxymethyl)-9-(2-phosphonylmethoxyethyl)adenine; C059141:verlukast; D019772:Topotecan; C028025:protoporphyrin IX; D000225:Adenine