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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Inhibition of mutant BRAF splice variant signaling by next- generation, selective RAF inhibitors
Pigment cell and melanoma research, v 27(3), pp 479-484
May 2014
PMID: 24422853
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Vemurafenib and dabrafenib block MEK-ERK1/2 signaling and cause tumor regression in the majority of advanced-stage BRAF(V600E) melanoma patients; however, acquired resistance and paradoxical signaling have driven efforts for more potent and selective RAF inhibitors. Next-generation RAF inhibitors, such as PLX7904 (PB04), effectively inhibit RAF signaling in BRAF(V600E) melanoma cells without paradoxical effects in wild-type cells. Furthermore, PLX7904 blocks the growth of vemurafenib-resistant BRAF(V600E) cells that express mutant NRAS. Acquired resistance to vemurafenib and dabrafenib is also frequently driven by expression of mutation BRAF splice variants; thus, we tested the effects of PLX7904 and its clinical analog, PLX8394 (PB03), in BRAF(V600E) splice variant-mediated vemurafenib-resistant cells. We show that paradox-breaker RAF inhibitors potently block MEK-ERK1/2 signaling, G1/S cell cycle events, survival and growth of vemurafenib/PLX4720-resistant cells harboring distinct BRAF(V600E) splice variants. These data support the further investigation of paradox-breaker RAF inhibitors as a second-line treatment option for patients failing on vemurafenib or dabrafenib.
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Details
- Title
- Inhibition of mutant BRAF splice variant signaling by next- generation, selective RAF inhibitors
- Creators
- Kevin J. Basile - Thomas Jefferson UniversityKaitlyn Le - Thomas Jefferson UniversityEdward J. Hartsough - Thomas Jefferson UniversityAndrew E. Aplin - Thomas Jefferson University
- Publication Details
- Pigment cell and melanoma research, v 27(3), pp 479-484
- Publisher
- Wiley
- Number of pages
- 6
- Grant note
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation P30CA056036; R01CA160495 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) CA160495 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA National Cancer Center Joanna M. Nicolay Melanoma Foundation P30CA56036 / National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000334170900018
- Scopus ID
- 2-s2.0-84898910552
- Other Identifier
- 991020531948204721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Cell Biology
- Dermatology
- Oncology