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Journal article
Response and Resistance to Paradox-Breaking BRAF Inhibitor in Melanomas In Vivo and Ex Vivo
Molecular cancer therapeutics, v 17(1), pp 84-95
01 Jan 2018
PMID: 29133617
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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. (C) 2017 AACR.
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Details
- Title
- Response and Resistance to Paradox-Breaking BRAF Inhibitor in Melanomas In Vivo and Ex Vivo
- Creators
- Edward J. Hartsough - Thomas Jefferson UniversityCurtis H. Kugel - Thomas Jefferson UniversityMichael J. Vido - Thomas Jefferson UniversityAdam C. Berger - Thomas Jefferson UniversityTimothy J. Purwin - Thomas Jefferson UniversityAllison Goldberg - Thomas Jefferson UniversityMichael A. Davies - College Station Medical CenterMatthew J. Schiewer - Thomas Jefferson UniversityKaren E. Knudsen - Thomas Jefferson UniversityGideon Bollag - Plexxikon IncAndrew E. Aplin - Thomas Jefferson University
- Publication Details
- Molecular cancer therapeutics, v 17(1), pp 84-95
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 12
- Grant note
- CA203314 / National Institutes of Health F30 fellowship Dr. Miriam and Sheldon G. Adelson Medical Research Foundation P30 CA56036 / National Cancer Institute Support Grant CA182635; CA196278; CA182569 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA F30CA203314 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) CA207855 / National Institutes of Health K99 grant CA16672 / NCI Cancer Center Support Grant; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) National Cancer Center
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000419148400008
- Scopus ID
- 2-s2.0-85040054957
- Other Identifier
- 991020531842704721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Oncology