Abstract
Abstract Purpose: BRAFV600-mutated melanoma brain metastases (MBMs) are generally responsive to BRAF and MEK inhibitors, albeit that responses are generally less durable than of extracranial metastases. We have studied the impact of the drug efflux proteins P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP; ABCG2) at the blood-brain barrier (BBB) on the efficacy of vemurafenib against BRAF-mutated A375 MBMs. Experimental design: We have implanted BRAF-mutated A375 tumor cells in the brains of wildtype and Abcb1a/b;Abcg2-/- mice. We characterized the BBB in the tumors, treated the mice with oral vemurafenib, analyzed drug levels in plasma and brain lesions and determined the efficacy in brain metastases and subcutaneous lesions. Results: Although A375 MBMs disrupt the integrity of the BBB, as shown by contrast-enhanced MRI, vemurafenib achieves greater antitumor efficacy in Abcb1a/b;Abcg2-/- mice compared to wild-type mice. P-gp and BCRP in brain tumor vessels limit vemurafenib penetration into A375 MBMs. Vemurafenib efficacy in both strains was similar against subcutaneous A375 tumors. Intriguingly, 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. Rather, MBMs likely resorted to non-canonical growth signaling, as target inhibition of canonical MAPK and PI3K pathway signaling components was maintained in resistant intracranial A375 tumors. Conclusions: In line with clinical data, BRAFV600E-positive MBMs are less responsive to vemurafenib. This is partly due to protection by the BBB, but also because they rapidly acquire further resistance by resorting to non-canonical growth signaling. Citation Format: Mark C. de Gooijer, Ping Zhang, Levi C. Buil, Stephan Freriks, Gang Li, Jos H. Beijnen, Olaf Van Tellingen. Acquired and intrinsic resistance to vemurafenib in BRAFv600e-driven melanoma brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-255.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
