American Association for Cancer Research
15357163mct170705-sup-186838_2_supp_4339729_gy1bsl.docx (9.45 MB)

Supplemental Tables 1-3 from Response and Resistance to Paradox-Breaking BRAF Inhibitor in Melanomas In Vivo and Ex Vivo

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journal contribution
posted on 2023-04-03, 16:02 authored by Edward J. Hartsough, Curtis H. Kugel, Michael J. Vido, Adam C. Berger, Timothy J. Purwin, Allison Goldberg, Michael A. Davies, Matthew J. Schiewer, Karen E. Knudsen, Gideon Bollag, Andrew E. Aplin

Supplemental Table 1: Patient data and treatment history Supplemental Table 2: PBRT #15 Ion Torrent results Supplemental Table 3: PBRT #16 Ion Torrent results


National Cancer Center

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FDA-approved BRAF inhibitors produce high response rates and improve overall survival in patients with BRAF V600E/K–mutant melanoma, but are linked to pathologies associated with paradoxical ERK1/2 activation in wild-type BRAF cells. To overcome this limitation, a next-generation paradox-breaking RAF inhibitor (PLX8394) has been designed. Here, we show that by using a quantitative reporter assay, PLX8394 rapidly suppressed ERK1/2 reporter activity and growth of mutant BRAF melanoma xenografts. Ex vivo treatment of xenografts and use of a patient-derived explant system (PDeX) revealed that PLX8394 suppressed ERK1/2 signaling and elicited apoptosis more effectively than the FDA-approved BRAF inhibitor, vemurafenib. Furthermore, PLX8394 was efficacious against vemurafenib-resistant BRAF splice variant–expressing tumors and reduced splice variant homodimerization. Importantly, PLX8394 did not induce paradoxical activation of ERK1/2 in wild-type BRAF cell lines or PDeX. Continued in vivo dosing of xenografts with PLX8394 led to the development of acquired resistance via ERK1/2 reactivation through heterogeneous mechanisms; however, resistant cells were found to have differential sensitivity to ERK1/2 inhibitor. These findings highlight the efficacy of a paradox-breaking selective BRAF inhibitor and the use of PDeX system to test the efficacy of therapeutic agents. Mol Cancer Ther; 17(1); 84–95. ©2017 AACR.

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