ABCG2 Transporter Expression Impacts Group 3 Medulloblastoma Response to Chemotherapy

While a small number of plasma membrane ABC transporters can export chemotherapeutic drugs and confer drug resistance, it is unknown if these transporters are expressed or functional in less therapeutically tractable cancers such as Group3 medulloblastoma (G3 MB). Herein we show that among this class of drug transporters only ABCG2 was expressed at highly increased levels in human G3 MB and a mouse model of this disease. In the mouse model, Abcg2 protein was expressed at the plasma membrane where it functioned as expected based on export of prototypical substrates. By screening ABC substrates against mouse G3 MB tumorspheres in vitro, we found that Abcg2 inhibition could potentiate responses to the clinically employed drug topotecan, producing a >9-fold suppression 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 to 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 Group3 medulloblastoma.