Acquired and intrinsic resistance to vemurafenib in BRAF(V600E) -driven melanoma brain metastases
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FEBS Open Bio - 2023 - Zhang - ...
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The Christie NHS Foundation Trust, Manchester, M20 4BX, UK.Issue Date
2023
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BRAFV600 -mutated melanoma brain metastases (MBMs) are responsive to BRAF inhibitors, but responses are generally less durable than those of extracranial metastases. We 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. We intracranially implanted A375 melanoma cells in wild-type and Abcb1a/b;Abcg2-/- mice, 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. Although contrast-enhanced MRI demonstrated that the integrity of the BBB is disrupted in A375 MBMs, vemurafenib achieved greater antitumor efficacy against MBMs in Abcb1a/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 expression of these transporters limited vemurafenib penetration into A375 MBMs. Although initially responsive, A375 MBMs rapidly developed therapy resistance, even in Abcb1a/b;Abcg2-/- mice, and this was unrelated to pharmacokinetic or target inhibition issues. Taken together, we demonstrate that both intrinsic and acquired resistance can play a role in MBMs.Citation
Zhang P, Kuil LE, Buil LCM, Freriks S, Beijnen JH, van Tellingen O, et al. Acquired and intrinsic resistance to vemurafenib in BRAF(V600E) -driven melanoma brain metastases. FEBS open bio. 2023 Nov 12. PubMed PMID: 37953496. Epub 2023/11/13. eng.Journal
FEBS Open BioDOI
10.1002/2211-5463.13730PubMed ID
37953496Additional Links
https://dx.doi.org/10.1002/2211-5463.13730Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1002/2211-5463.13730