Preclinical Development Active Efflux of Dasatinib from the Brain Limits Efficacy against Murine Glioblastoma: Broad Implications for the Clinical Use of Molecularly Targeted Agents

The importance of theblood–brain barrier inpreventing effectivepharmacotherapyof glioblastomahas been controversial. The controversy stems from the fact that vascular endothelial cell tight junctions are disrupted in the tumor, allowing some systemic drug delivery. P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) efflux drugs from brain capillary endothelial cells into the blood. We tested the hypothesis that although the tight junctions are "leaky" in the core of glioblastomas, active efflux limits drug delivery to tumorinfiltrated normal brain and consequently, treatment efficacy. Malignant gliomas were induced by oncogene transfer into wild-type (WT) mice or mice deficient for Pgp and BCRP (knockout, KO). Glioma-bearing mice were orally dosedwith dasatinib, a kinase inhibitor anddual BCRP/PgP substrate that is being currently tested in clinical trials. KOmice treated with dasatinib survived for twice as long asWTmice. Microdissection of the tumor core, invasive rim, andnormal brain revealed 2to 3-fold enhancement in dasatinib brain concentrations in KO mice relative to WT. Analysis of signaling showed that poor drug delivery correlated with the lack of inhibition of a dasatinib target, especially in normal brain. A majority of human glioma xenograft lines tested expressed BCRP or PgP and were sensitized to dasatinib by a dual BCRP/Pgp inhibitor, illustrating a second barrier to drug delivery intrinsic to the tumor itself. These data show that active efflux is a relevant obstacle to treating glioblastoma and provide a plausible mechanistic basis for the clinical failure of numerous drugs that are BCRP/Pgp substrates. Mol Cancer Ther; 11(10); 2183–92. 2012 AACR.