Acquired and intrinsic resistance to vemurafenib in BRAFV600E-driven melanoma brain metastases

Abstract

ABSTRACTPurposeBRAFV600-mutated melanoma brain metastases (MBMs) are responsive to BRAF inhibitors, but responses are generally less durable than those of extracranial metastases. We here tested the hypothesis that the drug efflux transporters P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP;ABCG2) expressed at the blood–brain barrier (BBB) offer MBMs protection from therapy.MethodsWe intracranially implanted A375 tumor cells in wild-type andAbcb1a/b;Abcg2-/-mice. We characterized the tumor BBB, analyzed drug levels in plasma and brain lesions after oral vemurafenib administration and determined the efficacy against brain metastases and subcutaneous lesions.ResultsAlthough contrast-enhanced MRI demonstrated that the integrity of the BBB is disrupted in A375 MBMs, vemurafenib achieved greater antitumor efficacy against MBMs inAbcb1a/b;Abcg2-/-mice compared to wild-type mice. Concordantly, P-gp and BCRP are expressed in MBM-associated brain endothelium both in patients and in A375 xenografts and limited vemurafenib penetration into A375 MBMs. Confirming the BBB-specific context of this protection, vemurafenib was equally effective against subcutaneous A375 tumors in WT andAbcb1a/b;Abcg2-/-mice. Intriguingly, although initially responsive, A375 MBMs rapidly developed therapy resistance, even inAbcb1a/b;Abcg2-/-mice, and this was unrelated to pharmacokinetic or target inhibition issues. Rather, MBMs likely resorted to noncanonical growth signaling, as target inhibition of canonical MAPK pathway signaling components was maintained in resistant intracranial A375 tumors.ConclusionsWe demonstrate that BRAFV600E-driven MBMs are partly intrinsically protected from vemurafenib by the BBB. Intriguingly, MBMs can also rapidly acquire resistancein situ, likely by resorting to non-canonical growth signaling.